leptin and Alzheimer-Disease

Alzheimer's disease (AD) is the most common type of dementia characterized by the deposition of amyloid beta (Aβ) plaques and tau-neurofibrillary tangles in the brain. Visceral obesity (VO) is usually associated with low-grade inflammation due to higher expression of pro-inflammatory cytokines by adipose tissue. The objective of the present review was to evaluate the potential link between VO and the development of AD. Tissue hypoxia in obesity promotes tissue injury, production of adipocytokines, and release of pro-inflammatory cytokines leading to an oxidative-inflammatory loop with induction of insulin resistance. Importantly, brain insulin signaling is involved in the pathogenesis of AD and lower cognitive function. Obesity and enlargement of visceral adipose tissue are associated with the deposition of Aβ. All of this is consonant with VO increasing the risk of AD through the dysregulation of adipocytokines which affect the development of AD. The activated nuclear factor kappa B (NF-κB) pathway in VO might be a potential link in the development of AD. Likewise, the higher concentration of advanced glycation end-products in VO could be implicated in the pathogenesis of AD. Taken together, different inflammatory signaling pathways are activated in VO that all have a negative impact on the cognitive function and progression of AD except hypoxia-inducible factor 1 which has beneficial and neuroprotective effects in mitigating the progression of AD. In addition, VO-mediated hypoadiponectinemia and leptin resistance may promote the progression of Aβ formation and tau phosphorylation with the development of AD. In conclusion, VO-induced AD is mainly mediated through the induction of oxidative stress, inflammatory changes, leptin resistance, and hypoadiponectinemia that collectively trigger Aβ formation and neuroinflammation. Thus, early recognition of VO by visceral adiposity index with appropriate management could be a preventive measure against the development of AD in patients with VO.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Cytokines; Humans; Leptin; Obesity; Obesity, Abdominal

Midlife obesity and late-life weight loss confer a greater risk for developing dementia and Alzheimer's disease (AD), but the exact mechanisms behind this phenomenon are currently unknown. The answer could lie on the involvement of gastrointestinal factors, such as adipokines (e.g., leptin, adiponectin, and resistin) and ghrelin. In this context, we conducted a pre-registered systematic review and meta-analysis of 42 cross-sectional and 13 longitudinal studies targeting the associations between leptin, adiponectin, resistin, and ghrelin and the prevalence of general dementia, AD, and mild cognitive impairment (MCI). We also examined the relationship between the four gastrointestinal factors and neurocognitive outcomes and AD-related cerebrospinal fluid biomarkers. Patients with AD had lower blood leptin and higher resistin levels than cognitively normal participants. Lower leptin and higher resistin were associated with higher degree of cognitive impairment. Additionally, lower late-life leptin levels might be associated with higher prospective risk of dementia and AD, although more studies are needed to corroborate this. Results in ghrelin and adiponectin were not conclusive, with age, sex distribution, obesity, and severity of dementia seemingly acting as moderators across several analyses. Our work might contribute to the identification of new preclinical blood markers of MCI and AD.

Topics: Adipokines; Adiponectin; Alzheimer Disease; Biomarkers; Cognitive Dysfunction; Cross-Sectional Studies; Ghrelin; Humans; Leptin; Obesity; Prospective Studies; Resistin

Microbiota dysbiosis and metabolic syndrome, consequences of a non-adequate diet, generate a feedback pathogenic state implicated in Alzheimer's disease development. The lower production of short chain fatty acids (SCFAs) under dysbiosis status leads to lipid homeostasis deregulation and decreases Angptl4 release and AMPK activation in the adipose tissue, promoting higher lipid storage (adipocyte hypertrophy) and cholesterol levels. Also, low SCFA generation reduces GPR41 and GPR43 receptor activation at the adipose tissue (increasing leptin release and leptin receptor resistance) and intestinal levels, reducing the release of GLP-1 and YPP. Therefore, lower satiety sensation and energy expenditure occur, promoting a weight gaining environment mediated by higher food intake and lipid storage, developing dyslipemia. In this context, higher glucose levels, together with higher free fatty acids in the bloodstream, promote glycolipotoxicity, provoking a reduction in insulin released, insulin receptor resistance, advanced glycation products (AGEs) and type 2 diabetes. Intestinal dysbiosis and low SCFAs reduce bacterial biodiversity, increasing lipopolysaccharide (LPS)-producing bacteria and intestinal barrier permeability. Higher amounts of LPS pass to the bloodstream (endotoxemia), causing a low-grade chronic inflammatory state characterized by higher levels of leptin, IL-1β, IL-6 and TNF-α, together with a reduced release of adiponectin and IL-10. At the brain and neuronal levels, the generated insulin resistance, low-grade chronic inflammation, leptin resistance, AGE production and LPS increase directly impact the secretase enzymes and tau hyperphosphorylation, creating an enabling environment for β-amyloid senile plaque and tau tangled formations and, as a consequence, Alzheimer's initiation, development and maintenance.

Topics: Alzheimer Disease; Diabetes Mellitus, Type 2; Dietetics; Dysbiosis; Humans; Insulin Resistance; Leptin; Lipopolysaccharides; Metabolic Syndrome; Microbiota

Obesity is a growing worldwide health problem, affecting many people due to excessive saturated fat consumption, lack of exercise, or a sedentary lifestyle. Leptin is an adipokine secreted by adipose tissue that increases in obesity and has central actions not only at the hypothalamic level but also in other regions and nuclei of the central nervous system (CNS) such as the cerebral cortex and hippocampus. These regions express the long form of leptin receptor LepRb, which is the unique leptin receptor capable of transmitting complete leptin signaling, and are the first regions to be affected by chronic neurocognitive deficits, such as mild cognitive impairment (MCI) and Alzheimer's Disease (AD). In this review, we discuss different leptin resistance mechanisms that could be implicated in increasing the risk of developing AD, as leptin resistance is frequently associated with obesity, which is a chronic low-grade inflammatory state, and obesity is considered a risk factor for AD. Key players of leptin resistance are SOCS3, PTP1B, and TCPTP whose signalling is related to inflammation and could be worsened in AD. However, some data are controversial, and it is necessary to further investigate the underlying mechanisms of the AD-causing pathological processes and how altered leptin signalling affects such processes.

Topics: Alzheimer Disease; Humans; Leptin; Obesity; Receptors, Leptin; Risk Factors

During aging, body adiposity increases with changes in the metabolism of lipids and their metabolite levels. Considering lipid metabolism, excess adiposity with increased lipotoxicity leads to various age-related diseases, including cardiovascular disease, cancer, arthritis, type 2 diabetes, and Alzheimer's disease. However, the multifaceted nature and complexities of lipid metabolism make it difficult to delineate its exact mechanism and role during aging. With advances in genetic engineering techniques, recent studies have demonstrated that changes in lipid metabolism are associated with aging and age-related diseases. Lipid accumulation and impaired fatty acid utilization in organs are associated with pathophysiological phenotypes of aging. Changes in adipokine levels contribute to aging by modulating changes in systemic metabolism and inflammation. Advances in lipidomic techniques have identified changes in lipid profiles that are associated with aging. Although it remains unclear how lipid metabolism is regulated during aging, or how lipid metabolites impact aging, evidence suggests a dynamic role for lipid metabolism and its metabolites as active participants of signaling pathways and regulators of gene expression. This review describes recent advances in our understanding of lipid metabolism in aging, including established findings and recent approaches.

Topics: Adiponectin; Adipose Tissue; Adiposity; Aging; Alzheimer Disease; Arthritis; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Fatty Acids; Gene Expression Regulation; Humans; Leptin; Lipid Metabolism; Lipidomics; Neoplasms; Obesity; Signal Transduction

Obesity and dementia are two growing problems worldwide. Obesity act as a crucial risk factor for various diseases including Alzheimer's disease (AD). Several preclinical studies showed that middle-age obesity can be act as a possible feature of mild cognitive impairment in later years. Some studies have also demonstrated that a high-fat diet causes AD pathology, including extracellular amyloid-beta accumulation, hyperphosphorylation of tau, and cognition impairment. The correlation and molecular mechanism related to obesity-associated AD needs to be better evaluated. Presently, obesity results in an altered expression of several hormones, growth factors, and adipokines. Multiple signaling pathways such as leptin, insulin, adiponectin, and glutamate are involved to regulate vital functions in the brain and act as neuroprotective mediators for AD in a normal state. In obesity, altered adiponectin (APN) level and its associated downstream pathway could result in multiple signaling pathway disruption. Presently, Adiponectin and its inducers or agonist are considered as potential therapeutics for obesity-associated AD. This review mainly focuses on the pleiotropic effects of adiponectin and its potential to treat obesity-associated AD.

Topics: Adiponectin; Alzheimer Disease; Animals; Humans; Insulin; Leptin; Obesity; Signal Transduction

Recent clinical and epidemiological observations point to a correlation between disorders of energy metabolism, such as obesity and diabetes, and cognitive decline and dementia. Many studies indicate that these age-related conditions closely interact with each other, but the underlying molecular and physiological mechanisms for such correlations are largely unknown. Insulin and leptin, hormones classically implicated in diabetes and obesity, are gaining increasing attention for their participation in cognitive processes and memory. Disrupted signaling by those hormones is associated with impaired brain function. The current review discusses how restoration of insulin and leptin signaling in the brain may attenuate neuronal damage and promote cognition. We further discuss potential therapeutic approaches involving the use of insulin and leptin as cognitive enhancers in the context of metabolic disorders and Alzheimer's disease. This article is part of the special issue entitled 'The Quest for Disease-Modifying Therapies for Neurodegenerative Disorders'.

Topics: Alzheimer Disease; Animals; Biomarkers; Energy Metabolism; Humans; Insulin; Leptin; Metabolic Diseases; Nootropic Agents

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder in the elderly population. Numerous epidemiological and experimental studies have demonstrated that patients who suffer from obesity or type 2 diabetes mellitus have a higher risk of cognitive dysfunction and AD. Several recent studies demonstrated that food intake-lowering (anorexigenic) peptides have the potential to improve metabolic disorders and that they may also potentially be useful in the treatment of neurodegenerative diseases. In this review, the neuroprotective effects of anorexigenic peptides of both peripheral and central origins are discussed. Moreover, the role of leptin as a key modulator of energy homeostasis is discussed in relation to its interaction with anorexigenic peptides and their analogs in AD-like pathology. Although there is no perfect experimental model of human AD pathology, animal studies have already proven that anorexigenic peptides exhibit neuroprotective properties. This phenomenon is extremely important for the potential development of new drugs in view of the aging of the human population and of the significantly increasing incidence of AD.

Topics: Alzheimer Disease; Animals; Appetite Depressants; Disease Models, Animal; Energy Metabolism; Homeostasis; Humans; Leptin; Neuroprotective Agents; Oligopeptides; Pyrrolidonecarboxylic Acid

Alzheimer's disease (AD) is an irreversible, progressive disease that slowly destroys cognitive function, such as thinking, remembering, and reasoning, to a level that one cannot carry out a daily living. As people live longer, the risk of developing AD has increased to 1 in 10 among people who are older than 65 and to almost 1 in 2 among those who are older than 85 according to a 2019 Alzheimer's Association report. As a most common cause of dementia, AD accounts for 60-80% of all dementia cases. AD is characterized by amyloid plaques and neurofibrillary tangles, composed of extracellular aggregates of amyloid-β peptides and intracellular aggregates of hyperphosphorylated tau, respectively. Besides plaques and tangles, AD pathology includes synaptic dysfunction including loss of synapses, inflammation, brain atrophy, and brain hypometabolism, all of which contribute to progressive cognitive decline. Recent genetic studies of sporadic cases of AD have identified a score of risk factors, as reported by Hollingworth et al. (Nat Genet 43:429-435, 2001) and Lambert et al. (Nat Genet 45:1452-1458, 2013). Of all these genes, apolipoprotein E4 (APOE4) still presents the biggest risk factor for sporadic cases of AD, as stated in Saunders et al. (Neurology 43:1467-1472, 1993): depending on whether you have 1 or 2 copies of APOE4 allele, the risk increases from 3- to 12-fold, respectively, in line with Genin et al. (Mol Psychiatry 16:903-907, 2011). Besides these genetic risk factors, having type 2 diabetes (T2D), a chronic metabolic disease, is known to increase the AD risk by at least 2-fold when these individuals age, conforming to Sims-Robinson et al. (Nat Rev Neurol 6:551-559, 2010). Diabetes is reaching a pandemic scale with over 422 million people diagnosed worldwide in 2014 according to World Health Organization. Although what proportion of these diabetic patients develop AD is not known, even if 10% of diabetic patients develop AD later in their life, it would double the number of AD patients in the world. Better understanding between T2D and AD is of paramount of importance for the future. The goal of this review is to examine our current understanding on metabolic dysfunction in AD, so that a potential target can be identified in the near future.

Topics: Alzheimer Disease; Animals; Brain; Chronobiology Disorders; Glucose; Humans; Leptin; Metabolic Diseases

Accumulating evidence indicates that diet and body weight are important factors associated with Alzheimer's disease (AD), with a significant increase in AD risk linked to mid-life obesity, and weight loss frequently occurring in the early stages of AD. This has fuelled interest in the hormone leptin, as it is an important hypothalamic regulator of food intake and body weight, but leptin also markedly influences the functioning of the hippocampus; a key brain region that degenerates in AD. Increasing evidence indicates that leptin has cognitive enhancing properties as it facilitates the cellular events that underlie hippocampal-dependent learning and memory. However, significant reductions in leptin's capacity to regulate hippocampal synaptic function occurs with age and dysfunctions in the leptin system are associated with an increased risk of AD. Moreover, leptin is a potential novel target in AD as leptin treatment has beneficial effects in various models of AD. Here we summarise recent advances in leptin neurobiology with particular focus on regulation of hippocampal synaptic function by leptin and the implications of this for neurodegenerative disorders like AD. This article is part of the Special Issue entitled 'Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.'

Topics: Alzheimer Disease; Animals; Hippocampus; Humans; Leptin

Leptin, as a link between fat mass and the brain, has been reported to be associated with gender. The gender differences in leptin levels between Alzheimer's disease (AD) and healthy elderly controls are inconclusive so far. To quantitatively summarize the leptin data available from female and male patients with AD, we searched PubMed and EMBASE for articles published from inception to July 20, 2017. Data were extracted from 27 studies, consisting of 3,014 participants. The pooled results showed that the overall leptin levels were lower in AD (Hedges' g = -0.481; p = 0.002) than in controls, and the leptin levels in whole blood and serum were decreased with moderate and large effect sizes (g = -0.677, -0.839; respectively; both of p-values <0.001) in AD compared with controls. In blood, there were significantly lower concentrations of leptin in female AD than in female controls (g = -0.590; p = 0.014), but not in male case-control group (g = -0.666; p = 0.067). Meta-regression analysis demonstrated that the decreased extent of leptin levels in AD paralleled the degree of the severity of dementia symptoms, as well as the alterations of body mass index (p-values ≤0.002). The findings provide strong evidence that 1) the blood concentrations of leptin are lower in female AD patients than in female controls; and 2) the greater the severity of dementia symptoms, the greater the decreases in the blood leptin levels. But more future investigations on the blood leptin levels in male AD patients is warranted.

Topics: Alzheimer Disease; Biomarkers; Female; Humans; Leptin; Male; Sex Characteristics

The ability of the brain to directly control glucose levels in the blood independently of its effects on food intake and body weight has been known ever since 1854 when Claude Bernard, a French physiologist, discovered that lesioning the floor of the fourth ventricle in rabbits led to a rise of sugar in the blood. Despite this outstanding discovery at that time, it took more than 140 years before progress started to be made in identifying the underlying mechanisms of brain-mediated control of glucose homeostasis. Technological advances including the generation of brain insulin receptor null mice revealed that insulin action specifically in the central nervous system is required for the regulation of glucose metabolism, particularly in the modulation of hepatic glucose production. Furthermore, it was established that the hormone leptin, known for its role in regulating food intake and body weight, actually exerts its most potent effects on glucose metabolism, and that this function of leptin is mediated centrally. Under certain circumstances, high levels of leptin can replicate the actions of insulin, thus challenging the idea that life without insulin is impossible. Disruptions of central insulin signaling and glucose metabolism not only lead to impairments in whole body glucose homeostasis, they also have other serious consequences, including the development of Alzheimer's disease which is sometimes referred to as type 3 diabetes reflecting its common etiology with type 2 diabetes. © 2017 American Physiological Society. Compr Physiol 7:471-764, 2017.

Topics: Alzheimer Disease; Animals; Blood Glucose; Diet, High-Fat; Fatty Acids; Homeostasis; Humans; Hypothalamic Diseases; Inflammation; Insulin; Leptin; Receptor, Insulin; Wnt Signaling Pathway

Observational evidence regarding the role of leptin in Alzheimer disease (AD) is conflicting. We sought to determine the causal role of circulating leptin and soluble plasma leptin receptor (sOB-R) levels in AD using a separate-sample Mendelian randomization study.. Single nucleotide polymorphisms (SNPs) independently and solely predictive of log-transformed leptin (rs10487505 [LEP], rs780093 [GCKR], rs900400 [CCNL1], rs6071166 [SLC32A1], and rs6738627 [COBLL1]) and of sOB-R (rs1137101 [LEPR], rs2767485 [LEPR], and rs1751492 [LEPR]) levels (ng/mL) were obtained from 2 previously reported genome-wide association studies. We obtained associations of leptin and sOB-R levels with AD using inverse variance weighting with fixed effects by combining Wald estimates for each SNP. Sensitivity analyses included using weighted median and MR-Egger methods and repeating the analyses using only SNPs of genome-wide significance.. Using inverse variance weighting, genetically predicted circulating leptin levels were not associated with AD, albeit with wide confidence intervals (CIs): odds ratio (OR) 0.99 per log-transformed ng/mL; 95% CI 0.55-1.78. Similarly, the association of sOB-R with AD was null using inverse variance weighting (OR 1.08 per log-transformed ng/mL; 95% CI 0.83-1.41). Results from our sensitivity analyses confirmed our findings.. In this first Mendelian randomization study estimating the causal effect of leptin on AD, we did not find an effect of genetically predicted circulating leptin and sOB-R levels on AD. As such, this study suggests that leptin is unlikely to be a major contributor to AD, although the wide CIs preclude a definitive assessment.

Topics: Alzheimer Disease; Genetic Predisposition to Disease; Humans; Leptin; Mendelian Randomization Analysis; Polymorphism, Single Nucleotide; Receptors, Leptin

Cancer and Alzheimer's disease (AD) are both associated with aging, but do not often occur together. Obesity is a shared risk factor for both diseases and may be involved in this curious clinical observation. Fat cells produce many active substances, including leptin and adiponectin; leptin has cancer stimulating and AD inhibiting properties, while adiponectin can inhibit cancer but stimulate AD.. To describe the opposing effects of leptin and adiponectin on cancer and AD, to outline signaling pathways involved in these effects and to suggest new research on effective control strategies for both diseases.. A review was conducted to document the inverse cancer/AD relationship and the role of excess body fat as a common risk factor. Previous studies have suggested the involvement of p53, Wnt and other cell signaling pathways in this inverse relationship. The opposing effects of leptin and adiponectin on these signaling pathways in cancer and AD were evaluated.. The inverse cancer/AD relationship is well documented, as is the role of excess body fat, especially central obesity, in increasing risk for both diseases. Leptin and adiponectin have opposing effects in cancer and AD mediated by signaling factors that influence apoptosis, angiogenesis, and other cell growth controls. Wnt and p53 are prominent among these signaling factors.. Opposing effects of leptin and adiponectin, mediated by specific cell signaling pathways, are involved in the inverse cancer/Ad relationship. Future research aimed at modifying the leptin/adiponectin ratio may lead to important treatment and control approaches in both cancer and AD.

Topics: Adiponectin; Alzheimer Disease; Animals; Humans; Leptin; Neoplasms; Risk Factors; Signal Transduction; Tumor Suppressor Protein p53

Age-related dementia is increasingly recognized as having a mixed pathology, with contributions from both cerebrovascular factors and pathogenic factors associated with Alzheimer's disease (AD). Furthermore, there is accumulating evidence that vascular risk factors in midlife, e.g., obesity, diabetes, and hypertension, increase the risk of developing late-life dementia. Since obesity and changes in body weight/adiposity often drive diabetes and hypertension, understanding the relationship between adiposity and age-related dementia may reveal common underlying mechanisms. Here we offer a brief appraisal of how changes in body weight and adiposity are related to both AD and dementia on vascular basis, and examine the involvement of two key adipocyte-derived hormones: leptin and adiponectin. The evidence suggests that in midlife increased body weight/adiposity and subsequent changes in adipocyte-derived hormones may increase the long-term susceptibility to dementia. On the other hand, later in life, decreases in body weight/adiposity and related hormonal changes are early manifestations of disease that precede the onset of dementia and may promote AD and vascular pathology. Understanding the contribution of adiposity to age-related dementia may help identify the underlying pathological mechanisms common to both vascular dementia and AD, and provide new putative targets for early diagnosis and therapy. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia, edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock.

Topics: Adipocytes; Adiponectin; Adipose Tissue; Adiposity; Age Factors; Alzheimer Disease; Animals; Dementia, Vascular; Humans; Leptin

There is accumulating evidence from epidemiological studies that changes in body weight are associated with Alzheimer's disease (AD) from mid-life obesity increasing the risk of developing AD to weight loss occurring at the earliest stages of AD. Therefore, factors that regulate body weight are likely to influence the development and progression of AD. The adipocyte-derived hormone leptin has emerged as a major regulator of body weight mainly by activating hypothalamic neural circuits. Leptin also has several pleotropic effects including regulating cognitive function and having neuroprotective effects, suggesting a potential link between leptin and AD. Here, we will examine the relationship between leptin and AD by reviewing the recent evidence from cellular and animal models to human studies. We present a model where leptin has a bidirectional role in AD. Not only can alterations in leptin levels and function worsen cognitive decline and progression of AD pathology, but AD pathology, in of itself, can disrupt leptin signaling, which together would lead to a downward spiral of progressive neurodegeneration and worsening body weight and systemic metabolic deficits. Collectively, these studies serve as a framework to highlight the importance of understanding the molecular mechanisms underlying the body weight and systemic metabolic deficits in AD, which has the potential to open new avenues that may ultimately lead to novel therapeutic targets and diagnostic tools.

Topics: Alzheimer Disease; Animals; Body Weight; Disease Models, Animal; Humans; Leptin; Neuroprotective Agents; Translational Research, Biomedical

Aging leads to a number of physiological alterations, specifically changes in circulating hormone levels, increases in fat deposition, decreases in metabolism, changes in inflammatory responses, and reductions in growth factors. These progressive changes in physiology and metabolism are exacerbated by modern culture and Western diet and give rise to diseases such as obesity, metabolic syndrome, and type 2 (non-insulin-dependent) diabetes (T2D). These age and lifestyle-related metabolic diseases are often accompanied by insulin and leptin resistance, as well as aberrant amylin production and signaling. Many of these alterations in hormone production and signaling are directly influenced by an increase in both oxidative stress and inflammation. Importantly, changes in hormone production and signaling have direct effects on brain function and the development of age-related neurologic disorders. Therefore, this review aims to present evidence on the effects that diet and metabolic disease have on age-related cognitive decline and the development of cognitive diseases, particularly Alzheimer disease. This review will focus on the metabolic hormones insulin, leptin, and amylin and their role in cognitive decline, as well as the therapeutic potential of these hormones in treating cognitive disease. Future investigations targeting the long-term effects of insulin and leptin treatment may reveal evidence to reduce risk of cognitive decline and Alzheimer disease.

Topics: Aging; Alzheimer Disease; Cognition; Cognitive Dysfunction; Diabetes Mellitus, Type 2; Humans; Insulin; Islet Amyloid Polypeptide; Leptin; Obesity

Receptors of leptin, the prototypical adipokine, are expressed throughout the cortex and several other areas of the brain. Although typically studied for its role in energy intake and expenditure, leptin plays a critical role in many other neurocognitive processes and interacts with various other hormones and neurotransmitters to perform these functions. Here, we review the literature on how leptin influences brain development, neural degradation, Alzheimer's disease, psychiatric disorders, and more complicated cognitive functioning and feeding behaviors. We also discuss modulators of leptin and the leptin receptor as they relate to normal cognitive functioning and may mediate some of the actions of leptin in the brain. Although we are beginning to better understand the critical role leptin plays in normal cognitive functioning, there is much to be discovered.

Topics: Alzheimer Disease; Animals; Brain; Cognition; Humans; Leptin; Mental Disorders; Receptors, Leptin

Leptin (Lep) is emerging as a pivotal molecule involved in both the early events and the terminal phases of Alzheimer's disease (AD). In the canonical pathway, Lep acts as an anorexigenic factor via its effects on hypothalamic nucleus. However, additional functions of Lep in the hippocampus and cortex have been unravelled in recent years. Early events in the sporadic form of AD likely involve cellular level alterations which can have an effect on food intake and metabolism. Thus, AD can be conceivably interpreted as a multiorgan pathology that not only results in a dramatic neuronal loss in brain areas such as the hippocampus and the cortex (ultimately leading to a significant cognitive impairment) but as a disease which also affects body-weight homeostasis. According to this view, body-weight control disruptions are to be expected in both the early- and late-stage AD, concomitant with changes in serum Lep content, alterations in Lep transport across the blood-brain barrier (BBB) and Lep receptor-related signalling abnormalities. Lep is a member of the adipokine family of molecules, while the Lep receptor belongs to the class I cytokine receptors. Since cellular response to adipokine signalling can be either potentiated or diminished as a result of specific ligand-receptor interactions, Lep interactions with other members of the adipokine family including amylin, ghrelin and hormones such as prolactin require further investigation. In this review, we provide a general perspective on the functions of Lep in the brain, with a particular focus on the sporadic AD.

Topics: Alzheimer Disease; Diabetes Mellitus, Type 2; Ghrelin; Humans; Hypothalamus; Islet Amyloid Polypeptide; Leptin; Life Style; Obesity; Prolactin; Protein Binding

Alzheimer's disease (AD) is the most common cause of progressive dementia in the elderly population. AD is histologically characterized by accumulation of amyloid-β protein (Aβ) on extracellular plaques and deposition of hyperphosphorylated tau protein in intracellular neurofibrillary tangles. Several studies have shown that obesity may precede dementia and that lifestyle factors play a critical role in the onset of AD. Furthermore, accumulating evidence indicates that obesity is an independent risk factor for developing AD. In this scenario, the understanding of the role of adipose tissue in brain health is essential to clarify the establishment of demential processes. The objective of this work was to review studies regarding leptin, an anorexigenic peptide hormone synthesized in adipocytes, in the context of dementia. Some authors proposed that leptin evaluation might be a better predictor of dementia than traditional anthropometric measures. Leptin, once established as a biomarker, could enhance the understanding of late-onset AD risk over the life course, as well as the clinical progression of prodromal state to manifested AD. Other studies have proposed that leptin presents neuroprotective activities, which could be explained by inhibiting the amyloidogenic process, reducing the levels of tau protein phosphorylation and improving the cognitive function.

Topics: Alzheimer Disease; Animals; Humans; Leptin; Phosphorylation; Polymorphism, Genetic; Receptors, Leptin

The insulin signaling system of the brain has a key role in the regulation of fundamental cell processes in neurons and controls metabolic processes in the CNS and periphery. In hypothalamic neurons insulin signaling system interacts closely with the other signaling systems regulated by leptin, melanocortin peptides, dopamine, serotonin, and is the key component of the hypothalamic signaling network, which integrates and transforms the central and peripheral signals. The disturbances in the brain insulin system lead to central insulin resistance, which is one of the primary causes of type 2 diabetes mellitus (DM), metabolic syndrome and Alzheimer's disease. The early restoration of the functions of this system provides an effective approach to prevent and treat type 2 DM and neurodegenerative diseases associated to it. In this review the literature data and own results on structural functional organization of the brain insulin signaling system, causes and functional consequences of central insulin resistance, abnormalities of insulin signaling in the CNS and approaches to its restoration in type 2 DM are analyzed and discussed.

Topics: Alzheimer Disease; Diabetes Mellitus, Type 2; Dopamine; Humans; Hypoglycemic Agents; Hypothalamus; Insulin; Insulin Resistance; Leptin; Melanocortins; Metabolic Syndrome; Neurons; Serotonin; Signal Transduction

The endocrine hormone leptin plays a key role in regulating food intake and body weight via its actions in the hypothalamus. However, leptin receptors are highly expressed in many extra-hypothalamic brain regions and evidence is growing that leptin influences many central processes including cognition. Indeed, recent studies indicate that leptin is a potential cognitive enhancer as it markedly facilitates the cellular events underlying hippocampal-dependent learning and memory, including effects on glutamate receptor trafficking, neuronal morphology and activity-dependent synaptic plasticity. However, the ability of leptin to regulate hippocampal synaptic function markedly declines with age and aberrant leptin function has been linked to neurodegenerative disorders such as Alzheimer's disease (AD). Here, we review the evidence supporting a cognitive enhancing role for the hormone leptin and discuss the therapeutic potential of using leptin-based agents to treat AD.

Topics: Age Factors; Alzheimer Disease; CA1 Region, Hippocampal; Cognition; Humans; Leptin; Long-Term Potentiation; Microfilament Proteins; Models, Neurological; Phosphoric Monoester Hydrolases; Protein Subunits; Receptors, AMPA; Synapses; Tensins

As the population of the world ages, the prevalence of neurodegenerative disease continues to rise, accompanied by increases in disease burden related to obesity and metabolic disorders. Thus, it will be essential to develop tools for preventing and slowing the progression of these major disease entities. Epidemiologic studies have shown strong associations between obesity, metabolic dysfunction, and neurodegeneration, while animal models have provided insights into the complex relationships between these conditions. Experimentally, the fat-derived hormone leptin has been shown to act as a neuroprotective agent in various animal models of dementia, toxic insults, ischemia/reperfusion, and other neurodegenerative processes. Specifically, leptin minimizes neuronal damage induced by neurotoxins and pro-apoptotic conditions. Leptin has also demonstrated considerable promise in animal models of obesity and metabolic disorders via modulation of glucose homeostasis and energy intake. However, since obesity is known to induce leptin resistance, we hypothesize that resistance to the neuroprotective effects of leptin contributes to the pathogenesis of obesity-associated neurodegenerative diseases. This review aims to explore the literature pertinent to the role of leptin in the protection of neurons from the toxic effects of aging, obesity and metabolic disorders, to investigate the physiological state of leptin resistance and its causes, and to consider how leptin might be employed therapeutically in the prevention and treatment of neurodegenerative disease.

Topics: Alzheimer Disease; Animals; Brain; Disease Models, Animal; Humans; Hypothalamus; Leptin; Mice; Neurons; Neuroprotective Agents; Obesity; Parkinson Disease; Rats

Alzheimer's disease (AD) is the most common cause of dementia, affecting more than 36 million people worldwide. AD is characterized by a progressive loss of cognitive functions. For years, it has been thought that age is the main risk factor for AD. Recent studies suggest that life style factors, including nutritional behaviors, play a critical role in the onset of dementia. Evidence about the relationship between nutritional behavior and AD includes the role of conditions such as obesity, hypertension, dyslipidemia and elevated glucose levels. The coexistence of some of these cardio-metabolic risk factors is generally known as metabolic syndrome (MS). Some clinical studies support the role of MS in the onset of AD. However, the cross-talk between the molecular signaling implicated in these disorders is unknown. In the present review, we focus on the molecular correlates that support the relationship between MS and the onset of AD. We also discuss relevant issues such as the role of leptin, insulin and renin-angiotensin signaling in the brain and the possible role of Wnt signaling in both MS and AD. We discuss the evidence supporting the use of ob/ob mice, high-fructose diets, aortic coarctation-induced hypertension and Octodon degus, which spontaneously develops β-amyloid deposits and metabolic derangements, as suitable animal models to address the relationships between MS and AD. Finally, we examine emergent data supporting the role of Wnt signaling in the modulation of AD and MS, implicating this pathway as a therapeutic target in both conditions.

Topics: Alzheimer Disease; Animals; Humans; Leptin; Metabolic Diseases; Wnt Signaling Pathway

Through their well described actions in the hypothalamus, appetitive peptides such as insulin, orexin and leptin are recognized as important regulators of food intake, body weight and body composition. Beyond these metabolic activities, these peptides also are critically involved in a wide variety of activities ranging from modulation of immune and neuroendocrine function to addictive behaviors and reproduction. The neurological activities of insulin, orexin and leptin also include facilitation of hippocampal synaptic plasticity and enhancement of cognitive performance. While patients with metabolic disorders such as obesity and diabetes have greater risk of developing cognitive deficits, dementia and Alzheimer's disease (AD), the underlying mechanisms that are responsible for, or contribute to, age-related cognitive decline are poorly understood. In view of the importance of these peptides in metabolic disorders, it is not surprising that there is a greater focus on their potential role in cognitive deficits associated with aging. The goal of this review is to describe the evidence from clinical and pre-clinical studies implicating insulin, orexin and leptin in the etiology and progression of age-related cognitive decline. Collectively, these studies support the hypothesis that leptin and insulin resistance, concepts normally associated with the hypothalamus, are also applicable to the hippocampus.

Topics: Aging; Alzheimer Disease; Animals; Appetite Regulation; Hippocampus; Humans; Insulin; Intracellular Signaling Peptides and Proteins; Leptin; Neuronal Plasticity; Neuropeptides; Orexins; Peptides

The more common sporadic form of Alzheimer disease (SAD) and the metabolic syndrome are two highly prevalent pathological conditions of Western society due to incorrect diet, lifestyle, and vascular risk factors. Due to the increasing aging of populations, prevalence of AD in western industrialized countries will rise in the near future and, thus, new knowledge in the area of molecular biology and epigenetics will probably help to reverse the neurodegenerative process. Recent data have suggested metabolic syndrome as an independent risk factor for SAD. Furthermore, biological plausibility for this relationship has been framed within the metabolic cognitive syndrome concept, and some authors designed SAD as a brain diabetes or diabetes 3. Then, impaired signaling of insulin and from some adipokines involved in the so called adipoinsular axis, like leptin, ghrelin or amylin could give a metabolic basis to explain the origin and progression of SAD. Thus, dipokines like leptin, ghrelin and amylin, or their mimetic compounds, could contribuite to inhibit apoptosis and inflammation processes and, thus, generate protective responses in the nervous system. Moreover, these adipokines might promote the activation of a cognitive process which may retard or even partially reverse selected aspects of Alzheimer's disease or ageing memory loss.

Topics: Adipokines; Alzheimer Disease; Animals; Brain; Diabetes Complications; Energy Metabolism; Ghrelin; Glucose; Humans; Islet Amyloid Polypeptide; Leptin; Metabolic Syndrome

Alzheimer's disease and other related neurodegenerative diseases are highly debilitating disorders that affect millions of people worldwide. Efforts towards developing effective treatments for these disorders have shown limited efficacy at best, with no true cure to this day being present. Recent work, both clinical and experimental, indicates that many neurodegenerative disorders often display a coexisting metabolic dysfunction which may exacerbate neurological symptoms. It stands to reason therefore that metabolic pathways may themselves contain promising therapeutic targets for major neurodegenerative diseases. In this review, we provide an overview of some of the most recent evidence for metabolic dysregulation in Alzheimer's disease, Huntington's disease, and Parkinson's disease, and discuss several potential mechanisms that may underlie the potential relationships between metabolic dysfunction and etiology of nervous system degeneration. We also highlight some prominent signaling pathways involved in the link between peripheral metabolism and the central nervous system that are potential targets for future therapies, and we will review some of the clinical progress in this field. It is likely that in the near future, therapeutics with combinatorial neuroprotective and 'eumetabolic' activities may possess superior efficacies compared to less pluripotent remedies.

Topics: Adiponectin; Alzheimer Disease; Body Weight; Brain-Derived Neurotrophic Factor; Ghrelin; Glucagon-Like Peptide 1; Glucose; Humans; Leptin; Metabolic Diseases; Neurodegenerative Diseases

AMP-activated protein kinase (AMPK) stimulates energy production via glucose and lipid metabolism, whereas it inhibits energy consuming functions, such as protein and cholesterol synthesis. Increased cytoplasmic AMP and Ca(2+) levels are the major activators of neuronal AMPK signaling. Interestingly, Alzheimer's disease (AD) is associated with several abnormalities in neuronal energy metabolism, for example, decline in glucose uptake, mitochondrial dysfunctions and defects in cholesterol metabolism, and in addition, with problems in maintaining Ca(2+) homeostasis. Epidemiological studies have also revealed that many metabolic and cardiovascular diseases are risk factors for cognitive impairment and sporadic AD. Emerging studies indicate that AMPK signaling can regulate tau protein phosphorylation and amyloidogenesis, the major hallmarks of AD. AMPK is also a potent activator of autophagic degradation which seems to be suppressed in AD. All these observations imply that AMPK is involved in the pathogenesis of AD. However, the responses of AMPK activation are dependent on stimulation and the extent of activating stress. Evidently, AMPK signaling can repress and delay the appearance of AD pathology but later on, with increasing neuronal stress, it can trigger detrimental effects that augment AD pathogenesis. We will outline the potential role of AMPK function in respect to various aspects affecting AD pathogenesis.

Topics: Alzheimer Disease; AMP-Activated Protein Kinases; Amyloid; Animals; Autophagy; Calcium; Enzyme Activation; Humans; Inflammation; Leptin; Metformin; Neurons; Phosphorylation; tau Proteins

Obesity has various deleterious effects on health largely associated with metabolic abnormalities including abnormal glucose and lipid homeostasis that are associated with vascular injury and known cardiac, renal, and cerebrovascular complications. Advanced age is also associated with increased adiposity, decreased lean mass, and increased risk for obesity-related diseases. Although many of these obesity- and age-related disease processes have long been subsumed to be secondary to metabolic or vascular dysfunction, increasing evidence indicates that obesity also modulates nonvascular diseases such as Alzheimer's disease (AD) dementia. The link between peripheral obesity and neurodegeneration will be explored, using adipokines and AD as a template. After an introduction to the neuropathology of AD, the relationship between body weight, obesity, and dementia will be reviewed. Then, population-based and experimental studies that address whether leptin modulates brain health and mitigates AD pathways will be explored. These studies will serve as a framework for understanding the role of adipokines in brain health.

Topics: Aging; Alzheimer Disease; Animals; Biomarkers; Body Weight; Brain; Disease Models, Animal; Female; Humans; Leptin; Male; Mice; Models, Neurological; Obesity; Receptors, Leptin; Risk Factors; Signal Transduction

Leptin is a pleiotropic hormone produced mainly by the adipose tissue. Its most well-known effect is to regulate food intake and energy metabolism within the hypothalamus. More recently, several peripheral and extra-hypothalamic effects have been described, expanding leptin's actions far beyond energy balance.. To review the extra-hypothalamic effects of leptin and their possible clinical implications.. We did a PubMed search using the terms "leptin" AND "brain" AND "neuron" AND "glial", and selected the most relevant articles.. In extra-hypothalamic sites, leptin has remarkable effects on neurogenesis, axon growth, synaptogenesis, denditric morphology, development of oligodendroglial cells, neuron excitability, neuroprotection and regulation of beta-amyloid levels. Those effects have been shown to improve cognition and mood in animal models of depression and anxiety. In lean humans, leptin levels have been negatively correlated with the development of Alzheimer's disease.. Leptin has extra-hypothalamic effects that may protect the brain against the development of mood and neurodegenerative disorders, such as Alzheimer's disease. Better understanding of those effects may lead to the development of potential leptin-based therapies against such conditions.

Topics: Alzheimer Disease; Brain; Cognition; Humans; Leptin; Obesity

Adipocyte-derived leptin appears to regulate a number of features defining Alzheimer's disease (AD) at the molecular and physiological level. Leptin has been shown to reduce the amount of extracellular amyloid beta, both in cell culture and animal models, as well as to reduce tau phosphorylation in neuronal cells. Importantly, chronic administration of leptin resulted in a significant improvement in the cognitive performance of transgenic animal models. In AD, weight loss often precedes the onset of dementia and the level of circulating leptin is inversely proportional to the severity of cognitive decline. It is speculated that a deficiency in leptin levels or function may contribute to systemic and CNS abnormalities leading to disease progression. Furthermore, a leptin deficiency may aggravate insulin-controlled pathways, known to be aberrant in AD. These observations suggest that a leptin replacement therapy may be beneficial for these patients.

Topics: Alzheimer Disease; Animals; Humans; Leptin

Novel approaches in the understanding of the neurodegeneration observed in Alzheimer's disease (AD), involving neurochemical as well as biochemical techniques are being developed, opening up new possibilities in the direction of a metabolic degeneration. Indeed, brain lipids are closely involved in amyloid beta-related pathogenic pathways. An important modulator of lipid homeostasis is the pluripotent peptide leptin, which has been shown to reduce amyloid beta levels and tau-related pathological pathways, the major pathological hallmarks of AD. These data suggest that leptin holds promise as a novel therapeutic tool for AD. In this article, with some patent literature we will review here some of the most promising approaches involving leptin to cure and prevent, rather than to treat, AD symptoms.

Topics: Alzheimer Disease; Animals; Drug Design; Drugs, Investigational; Humans; Leptin; Patents as Topic

Acquired disturbances of several aspects of cellular metabolism appear pathologically important in sporadic Alzheimer's disease (SAD). Among these, brain glucose utilization is reduced in the early stages of the disease. Hyperinsulinemia, which is a characteristic finding of insulin resistance, results in a central insulin deficit. Insufficient insulin signaling impairs the intricate balance of nitric oxide regulation of the central nervous system. Reduction in central insulin decreases neuronal nitric oxide synthase and increases inducible synthase activity. This, in turn, decreases astrocytic energy substrates and antioxidant supply of neurons. In addition, an increase in peroxynitrite formation impairs redox balance. Hyperleptinemia and glucose excess, which are the other parameters of insulin resistance, may worsen the reduced astrocytic energy supply and the ongoing inflammation via the inhibition of AMP-activated protein kinase (AMPK). Consequently, energy deficit and inflammation in neuronal tissue may cause neurodegeneration of SAD.

Topics: Alzheimer Disease; AMP-Activated Protein Kinases; Antioxidants; Astrocytes; Blood-Brain Barrier; Brain; Cerebral Amyloid Angiopathy; Diabetes Mellitus; Glucose; Humans; Inflammation; Insulin Resistance; Ketones; Leptin; Liver; Mitochondrial Diseases; Multienzyme Complexes; Nerve Degeneration; Oxidation-Reduction; Peroxynitrous Acid; Protein Serine-Threonine Kinases

Proteomic analysis is not limited to the analysis of serum or tissues. Synovial, peritoneal, pericardial and cerebrospinal fluid represent unique proteomes for disease diagnosis and prognosis. In particular, cerebrospinal fluid serves as a rich source of putative biomarkers that are not solely limited to neurologic disorders. Peptides, proteolytic fragments and antibodies are capable of crossing the blood-brain barrier, thus providing a repository of pathologic information. Proteomic technologies such as immunoblotting, isoelectric focusing, 2D gel electrophoresis and mass spectrometry have proven useful for deciphering this unique proteome. Cerebrospinal fluid proteins are generally less abundant than their corresponding serum counterparts, necessitating the development and use of sensitive analytical techniques. This review highlights some of the promising areas of cerebrospinal fluid proteomic research and their clinical applications.

Topics: Alzheimer Disease; Biomarkers; Brain Injuries; Brain Ischemia; Cerebrospinal Fluid Proteins; Cerebrospinal Fluid Rhinorrhea; Creutzfeldt-Jakob Syndrome; Dementia; Humans; Leptin; Low Back Pain; Moyamoya Disease; Multiple Sclerosis; Neurodegenerative Diseases; Nutrition Disorders; Paraneoplastic Cerebellar Degeneration; Parkinson Disease; Polymorphism, Genetic; Proteomics; Schizophrenia; Signal Transduction

Throughout the natural progression of Alzheimer's disease (AD), the body mass index (BMI) decreases. This is believed to be brought on by the disturbance in the central lipid metabolism, but the exact mechanism is yet unknown. Adipokines (adiponectin, leptin), hormones produced by the adipose tissue, change glucose and lipid metabolism, and have an anorectic effect through increasing energy consumption in the hypothalamus. The goal of our study was to examine donepezil - an acetylcholinesterase inhibitor (AChEI) currently used in AD therapy -, and to what degree it influences the serum adipokine levels and metabolic parameters of AD patients. During the self-evaluation of 26 clinically diagnosed mild to moderate AD patients, therapy with 10 mg/day donepezil was started according to current protocols. We measured serum adiponectin, leptin, LDL, HDL, trigliceride levels, and BMI and ApoE polymorphism at the beginning of our study, and at 3 and 6-months intervals respectively. All data were analyzed with SPSS 17. In comparison with pre-donepezil therapy values, at the third month interval serum adiponectin levels showed an increasing and leptin levels a decreasing tendency. At the six month interval, adiponectin levels significantly increased (p=0.007), leptin levels decreased (p=0.013), BMI (p=0.001) and abdominal circumference (p=0.017) was significantly lower at 6 months as compared to control values. We did not observe any changes in the lipid profile, and ApoE4 allele carrying showed no association with the parameters. To our knowledge, we are the first to publish that AChEI therapy with donepezil alters lipokine levels, which positively influences the currently known pathomechanism and numerous risk factors of AD. The AChEI treatment-induced weight loss should be considered in the long-term therapy of AD patients.

Topics: Adipokines; Adiponectin; Aged; Aged, 80 and over; Alzheimer Disease; Apolipoproteins E; Appetite; Biomarkers; Body Mass Index; Cholesterol, HDL; Cholesterol, LDL; Cholinesterase Inhibitors; Donepezil; Drug Administration Schedule; Female; Humans; Hungary; Indans; Leptin; Lipid Metabolism; Male; Middle Aged; Nootropic Agents; Outpatients; Piperidines; Polymorphism, Single Nucleotide; Severity of Illness Index; Time Factors; Treatment Outcome; Triglycerides; Waist Circumference

Adipokines such as leptin and adiponectin are associated with cognitive function. Although adiposity crucially affects adipokine levels, it remains unclear whether the relationship between adipokines and cognition is influenced by obesity.. We enrolled 171 participants and divided them into participants with obesity and without obesity to explore the effect of obesity on the relationship between adipokines and cognition. In addition to plasma levels of leptin and adiponectin, multidomain cognitive functions and brain structures were assessed using neuropsychological testing and magnetic resonance imaging. Association between levels of these adipokines and Alzheimer's disease (AD) was then assessed by logistic regression.. We found that cognitive function was negatively associated with leptin levels and leptin-to-adiponectin ratio (LAR). Such correlations between leptin and cognitive domains were prominent in participants with obesity but were not observed in those without obesity. Leptin levels were associated with lower hippocampal volumes in participants with obesity. A significant interaction of leptin and obesity was found mostly in the medial temporal lobe. Both leptin and LAR were positively associated with insulin resistance and inflammation markers in all participants. Of note, LAR was associated with a higher risk of AD after adjusting for demographic variables, Apolipoprotein E genotype, and body mass index.. Obesity might be a factor that determines how adipokines affect brain structure and cognition. Leptin resistance might influence the relationship between adipokines and cognition. In addition, LAR rather than each adipokine levels alone may be a better indicator of AD risk in older adults with metabolic stress.

Topics: Adipokines; Adiponectin; Aged; Alzheimer Disease; Brain; Cognition; Humans; Leptin; Obesity

Key pathological features of Alzheimer's disease (AD) include build-up of amyloid β (Aβ), which promotes synaptic abnormalities and ultimately leads to neuronal cell death. Metabolic dysfunction is known to influence the risk of developing AD. Impairments in the leptin system have been detected in AD patients, which has fuelled interest in targeting this system to treat AD. Increasing evidence supports pro-cognitive and neuroprotective actions of leptin and these beneficial effects of leptin are mirrored by a bioactive leptin fragment (leptin

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Alzheimer Disease; Amyloid beta-Peptides; Animals; Disease Models, Animal; Hippocampus; Humans; Leptin; Neuronal Plasticity; Receptors, AMPA

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloidogenic Proteins; Biomarkers; Humans; Leptin; tau Proteins

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloidogenic Proteins; Biomarkers; Humans; Leptin

The correlation between plasma adipose factor levels and Alzheimer's patients is not entirely clear.. We aimed to investigate associations between AD and plasma levels of three adipokines including plasma adiponectin, leptin, and resistin.. A single-center, cross-sectional study recruited AD patients (n = 148) and cognitively normal (CN) controls (n = 110). The multivariate logistic regression analysis was applied to determine associations of adiponectin, leptin, and resistin with the presence of AD. The receiver operating characteristic (ROC) analysis was employed to determine the diagnostic power of adiponectin, leptin and resistin for AD.. After adjusted for the conventional risk factors, plasma levels of leptin (OR = 0.417, 95% CI: 0.272-0.638, p < 0.0001) and adiponectin (OR = 1.249, 95% CI: 1.151-1.354, p < 0.0001) were associated with the presence of AD. In total participants, the plasma adiponectin level was negatively correlated with MMSE scores (p < 0.0001) and was positively with CDR scores (p < 0.0001) and age (p < 0.0001). The plasma level of leptin was negatively correlated with CDR scores (p < 0.0001) and positively correlated with MMSE scores (p < 0.0001). Both adiponectin (p < 0. 0001) and leptin (p < 0. 0001) featured higher AUC than the random chance.. Plasma adiponectin and leptin were associated with the presence, symptomatic severity, and diagnostic power of AD, suggesting a potential role of adipokines in the pathogenesis of AD.

Topics: Adipokines; Adiponectin; Alzheimer Disease; Cross-Sectional Studies; East Asian People; Humans; Leptin; Resistin

Amyloid-β (Aβ) and hyper-phosphorylated tau are key hallmarks of Alzheimer's disease (AD), with an accumulation of both proteins linked to hippocampal synaptic dysfunction. Recent evidence indicates that Aβ drives mis-localisation of tau from axons to synapses, resulting in AMPA receptor (AMPAR) internalisation and impaired excitatory synaptic function. These tau-driven synaptic impairments are thought to underlie the cognitive deficits in AD. Consequently, limiting the synapto-toxic effects of tau may prevent AD-related cognitive deficits. Increasing evidence links leptin dysfunction with higher AD risk, and numerous studies have identified neuroprotective properties of leptin in AD models of Aβ-induced toxicity. However, it is unclear if leptin protects against tau-related synaptic dysfunction. Here we show that Aβ

Topics: Alzheimer Disease; Amyloid beta-Peptides; Glycogen Synthase Kinase 3 beta; Hippocampus; Humans; Leptin; Phosphatidylinositol 3-Kinases; Phosphorylation; Synapses; tau Proteins

Metabolic dysfunction links to cognitive deficits in Alzheimer's disease (AD). Leptin is an anti-obesity hormone that modulates energy homeostasis and memory function. Although leptin deregulation is implicated in mouse models of AD-like brain pathology, clinical studies have shown inconsistent results regarding an association of leptin with the development of this neurodegenerative disorder.. We investigated the changes of plasma leptin and the correlation of sex-stratified circulating leptin with cognitive performance, AD-related biological markers, and metabolic status in patients with AD and cognitively unimpaired (CU) counterparts.. We used nonobese AD patients and CU controls in a University of Kansas Medical Center (KUMC) cohort. Plasma leptin levels, circulating AD-related molecules and metabolic profiles were examined and analyzed.. In contrast to unchanged circulating leptin in females, male patients exhibited decreased plasma leptin levels compared with male CU counterparts. Moreover, plasma leptin showed no correlation with cognitive performance and AD blood biomarkers in patients with either sex. Of note, females but not males demonstrated an association of plasma leptin with body mass index, high density lipoprotein-cholesterol and its ratio with total cholesterol and triglycerides.. Our findings suggest that leptin deficiency is associated with nonobese male AD patients, supporting systemic dysmetabolism in the development of this neurodegenerative disorder in certain populations. Although plasma leptin may have limited capacity to reflect disease severity or progression, future mechanistic studies on the regulation of leptin in nonobese patients with AD would deepen our understanding of the sex-related disparity of AD etiopathogenesis.

Topics: Alzheimer Disease; Animals; Biomarkers; Body Mass Index; Cholesterol, HDL; Female; Humans; Leptin; Mice

Blood adiponectin and leptin are adipokines that emerged as potential biomarkers for predicting Alzheimer's disease (AD) owing to their strong connection with obesity. Although obesity affects the relation between beta-amyloid (Aβ) aggregation and cognitive decline, the longitudinal interactive effect of adipokines and Aβ on cognition and brain structures in humans remains unexplored. Hence, we investigated whether plasma levels of adiponectin and leptin are associated with future cognitive decline and cortical thinning across Aβ conditions (Aβ [+] and Aβ [-]) in individuals with mild cognitive impairment (MCI).. Of 156 participants with MCI from the longitudinal cohort study of Alzheimer's Disease Neuroimaging Initiative (ADNI), 31 were Aβ (-) and 125 were Aβ (+) as determined by CSF analysis. The Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) scores and the thickness of the parahippocampal and entorhinal cortices were used to evaluate cognition and brain structure, respectively. After stratifying groups by Aβ conditions, the association of cognitive and brain structural changes with baseline plasma levels of adiponectin and leptin was examined.. Of the total 156 participants, 51 were women (32.7%). The mean age of participants was 74.5 (standard deviation 7.57), and the mean follow-up period was 54.3 months, without a difference between the Aβ (+) and (-) groups. After adjustment for confounders, higher plasma adiponectin levels were associated with a faster increase in ADAS-Cog scores, indicating faster cognitive decline under the Aβ (+) condition (beta = 0.224, p = 0.018). Likewise, participants with higher plasma adiponectin presented faster cortical thinning in the bilateral parahippocampal cortices under the Aβ (+) condition (beta = - 0.004, p = 0.012 for the right side; beta = - 0.004, p = 0.025 for the left side). Interestingly, plasma adiponectin levels were not associated with longitudinal ADAS-Cog scores or cortical thickness in the Aβ (-) condition. Plasma leptin levels were not predictive of cognition or cortical thickness regardless of Aβ status.. Plasma adiponectin can be a potential biomarker for predicting the speed of AD progression in individuals with Aβ (+) MCI.

Topics: Adiponectin; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Cerebral Cortical Thinning; Cognitive Dysfunction; Female; Humans; Leptin; Longitudinal Studies; Male; Obesity

The close relationship between Alzheimer's disease (AD) and obesity was recognized many years ago. However, complete understanding of the pathological mechanisms underlying the interactions between degeneration of CNS and fat metabolism is still missing. The leptin a key adipokine of white adipose tissue has been suggested as one of the major mediators linking the obesity and AD. Here we investigated the association between peripheral levels of leptin, general metabolic status and stage of the pathogenesis in rat transgenic model of AD. We demonstrate significantly decreased levels of plasma leptin in animals with experimentally induced progressive neurofibrillary pathology, which represents only 62.3% (P = 0.0015) of those observed in normal wild type control animals. More detailed analysis showed a strong and statistically significant inverse correlation between the load of neurofibrillary pathology and peripheral levels of leptin (r = - 0.7248, P = 0.0177). We also observed a loss of body weight during development of neurodegeneration (about 14% less than control animals, P = 0.0004) and decrease in several metabolic parameters such as glucose, insulin, triglycerides and VLDL in plasma of the transgenic animals. Our data suggest that plasma leptin could serve as a convenient peripheral biomarker for tauopathies and Alzheimer's disease. Decrease in gene expression of leptin in fat tissue and its plasma level was found as one of the consequences of experimentally induced neurodegeneration. Our data may help to design rational diagnostic and therapeutic strategies for patients suffering from Alzheimer's disease or other forms of tauopathy.

Topics: Alzheimer Disease; Animals; Disease Models, Animal; Humans; Leptin; Obesity; Rats; tau Proteins; Tauopathies

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia. While cognitive deficits remain the major manifestation of AD, metabolic and non-cognitive abnormalities, such as alterations in food intake, body weight and energy balance are also present, both in AD patients and animal models. In this sense, the tauroursodeoxycholic acid (TUDCA) has shown beneficial effects both in reducing the central and cognitive markers of AD, as well as in attenuating the metabolic disorders associated with it. We previously demonstrated that TUDCA improves glucose homeostasis and decreases the main AD neuromarkers in the streptozotocin-induced AD mouse model (Stz). Besides that, TUDCA-treated Stz mice showed lower body weight and adiposity. Here, we investigated the actions of TUDCA involved in the regulation of body weight and adiposity in Stz mice, since the effects of TUDCA in hypothalamic appetite control and energy homeostasis have not yet been explored in an AD mice model. The TUDCA-treated mice (Stz + TUDCA) displayed lower food intake, higher energy expenditure (EE) and respiratory quotient. In addition, we observed in the hypothalamus of the Stz + TUDCA mice reduced fluorescence and gene expression of inflammatory markers, as well as normalization of the orexigenic neuropeptides AgRP and NPY expression. Moreover, leptin-induced p-JAK2 and p-STAT3 signaling in the hypothalamus of Stz + TUDCA mice was improved, accompanied by reduced acute food intake after leptin stimulation. Taken together, we demonstrate that TUDCA treatment restores energy metabolism in Stz mice, a phenomenon that is associated with reduced food intake, increased EE and improved hypothalamic leptin signaling. These findings suggest treatment with TUDCA as a promising therapeutic intervention for the control of energy homeostasis in AD individuals.

Topics: Adiposity; Alzheimer Disease; Animals; Biomarkers; Body Weight; Disease Management; Disease Models, Animal; Energy Metabolism; Gene Expression; Homeostasis; Immunohistochemistry; Inflammation Mediators; Leptin; Male; Mice; Organ Specificity; Signal Transduction; Streptozocin; Taurochenodeoxycholic Acid; Thermogenesis

Metabolic dysfunction is now recognized as a pivotal component of Alzheimer's disease (AD), the most common dementia worldwide. However, the precise molecular mechanisms linking metabolic dysfunction to AD remain elusive.. Here, we investigated the direct impact of soluble oligomeric amyloid beta (Aβ) peptides, the main molecular hallmark of AD, on the leptin system, a major component of central energy metabolism regulation.. We developed a new time-resolved fluorescence resonance energy transfer-based Aβ binding assay for the leptin receptor (LepR) and studied the effect of Aβ on LepR function in several in vitro assays. The in vivo effect of Aβ on LepR function was studied in an Aβ-specific AD mouse model and in pro-opiomelanocortin (POMC) neurons of the hypothalamic arcuate nucleus.. We revealed specific and high-affinity (Ki = 0.1 nM) binding of Aβ to LepR. Pharmacological characterization of this interaction showed that Aβ binds allosterically to the extracellular domain of LepR and negatively affects receptor function. Negative allosteric modulation of LepR by Aβ was detected at the level of signaling pathways (STAT-3, AKT, and ERK) in vitroand in vivo. Importantly, the leptin-induced response of POMC neurons, key players in the regulation of metabolic function, was completely abolished in the presence of Aβ.. Our data indicate that Aβ is a negative allosteric modulator of LepR, resulting in impaired leptin action, and qualify LepR as a new and direct target of Aβ oligomers. Preventing the interaction of Aβ with LepR might improve both the metabolic and cognitive dysfunctions in AD condition.

Topics: Allosteric Regulation; Alzheimer Disease; Amyloid beta-Peptides; Animals; Arcuate Nucleus of Hypothalamus; Cell Line; Disease Models, Animal; HEK293 Cells; Humans; Leptin; Male; Mice; Pro-Opiomelanocortin; Receptors, Leptin; Signal Transduction

Alzheimer's disease (AD) is the most common dementia worldwide and is characterized by the presence of senile plaques by amyloid-beta (Aβ) and neurofibrillary tangles of hyperphosphorylated Tau protein. These changes lead to progressive neuronal degeneration and dysfunction, resulting in severe brain atrophy and cognitive deficits. With the discovery that neurogenesis persists in the adult mammalian brain, including brain regions affected by AD, studies of the use of neural stem cells (NSCs) for the treatment of neurodegenerative diseases to repair or prevent neuronal cell loss have increased. Here we demonstrate that leptin administration increases the neurogenic process in the dentate gyrus of the hippocampus as well as in the subventricular zone of lateral ventricles of adult and aged mice. Chronic treatment with leptin increased NSCs proliferation with significant effects on proliferation and differentiation of newborn cells. The expression of the long form of the leptin receptor, LepRb, was detected in the neurogenic niches by reverse qPCR and immunohistochemistry. Moreover, leptin modulated astrogliosis, microglial cell number and the formation of senile plaques. Additionally, leptin led to attenuation of Aβ-induced neurodegeneration and superoxide anion production as revealed by Fluoro-Jade B and dihydroethidium staining. Our study contributes to the understanding of the effects of leptin in the brain that may lead to the development of new therapies to treat Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cell Proliferation; Disease Models, Animal; Gliosis; Hippocampus; Humans; Lateral Ventricles; Leptin; Mice; Microglia; Neural Stem Cells; Neurogenesis; Plaque, Amyloid; Receptors, Leptin; Superoxides

High-fat and high-sugar diets contribute to the prevalence of type 2 diabetes and Alzheimer's disease (AD). Although the impact of high-fat diets on AD pathogenesis has been established, the effect of high-sucrose diets (HSDs) on AD pathogenesis remains unclear. This study sought to determine the impact of HSDs on AD-related pathologies. Male APPswe/PS1dE9 (APP/PS1) transgenic and wild-type mice were provided with HSD and their cognitive and hypothalamus-related noncognitive parameters, including feeding behaviors and glycemic regulation, were compared. HSD-fed APP/PS1 mice showed increased neuroinflammation, as well as increased cortical and serum levels of amyloid-β. HSD-fed APP/PS1 mice showed aggravated obesity, hyperinsulinemia, insulin resistance, and leptin resistance, but there was no induction of hyperphagia or hyperleptinemia. Leptin-induced phosphorylation of signal transducer and activator of transcription 3 in the dorsomedial and ventromedial hypothalamus was reduced in HSD-fed APP/PS1 mice, which might be associated with attenuated food-anticipatory activity, glycemic dysregulation, and AD-related noncognitive symptoms. Our study demonstrates that HSD aggravates metabolic stresses, increases AD-related pathologies, and attenuates hypothalamic leptin signaling in APP/PS1 mice.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Anticipation, Psychological; Diet, Carbohydrate Loading; Eating; Hypothalamus; Inflammation; Leptin; Mice, Transgenic; Signal Transduction; STAT3 Transcription Factor; Sucrose

Topics: Acer; Adipokines; Adiponectin; Administration, Ophthalmic; Alzheimer Disease; Amyloid Precursor Protein Secretases; Amyloidosis; Animals; Brain; Diet, High-Fat; Disease Models, Animal; Leptin; Obesity; Phytotherapy; Plant Extracts; Presenilin-1; Quercetin

Peripheral insulin resistance is associated with decreasing adiponectin and increasing leptin plasma levels, and also with cognitive decline. The effects of adipokines on brain function have been published from both animal and human studies. In particular, the influence of leptin and adiponectin on the development of Alzheimer's disease (AD) has been extensively investigated. However, the association between adipsin and AD is as yet unknown. In 37 patients with AD and 65 controls that followed the same study protocol, we tested whether adiponectin, leptin, and adipsin could be used as biomarkers in the early stages of AD. In contrast with conclusions of cognition studies in insulin resistant states, our study found a correlation of impaired neuropsychological performance with increasing adiponectin and decreasing leptin in AD patients. Nevertheless, no significant differences between patients and controls were found. AD women had significantly increased adipsin compared to controls, and there was a positive correlation of adipsin with age and disease duration. Although adipokines do not appear to be suitable biomarkers for early AD diagnosis, they certainly play a role in the pathogenesis of AD. Further studies will be needed to explain the cause of the adipokine "breaking point" that leads to the pathogenesis of overt AD.

Topics: Adiponectin; Alzheimer Disease; Biomarkers; Case-Control Studies; Complement Factor D; Female; Humans; Leptin; Male; Middle Aged

Recent evidence suggests that insulin resistance may play an important role in the pathogenesis of Alzheimer's disease (AD). In this study, the probable role of insulin resistance in the pathogenesis of AD was investigated in patients with Type 2 Diabetes Mellitus (T2DM).. Serum amyloid beta (Aβ) (1-42), insulin like growth factor-1 (IGF-1), sirtuin1 (SIRT1) and leptin protein levels were measured in serum samples of control (n = 26), probable AD (n = 26), and probable AD+T2DM patients (n = 12) using ELISA method. Mini mental state examination (MMSE) was performed to the patient and control groups.. Serum IGF-1 significantly increased in the probable AD+T2DM group as compared to the control and probable AD groups (p ˂ 0.05). The levels of serum leptin significantly decreased in the probable AD and AD+T2DM groups as compared to the control (p ˂ 0.05). There were no statistically significant differences in serum Aβ (1-42) and SIRT1 levels among groups (p > 0.05).. The significant decrease in serum leptin levels in AD patients may indicate that it may be a therapeutic marker in AD. The level of serum Aβ peptide and SIRT1 proteins can vary depending on the stage of the disease. Therefore, this study should be supported by more comprehensive studies in terms of the number of patients in advanced stage (Tab. 1, Fig. 4, Ref. 29).

Topics: Alzheimer Disease; Amyloid beta-Peptides; Diabetes Mellitus, Type 2; Humans; Insulin Resistance; Leptin; Sirtuin 1

Alzheimer's disease (AD) has challenged single-target therapeutic strategies, raising the possibility that combined therapies may offer a more effective treatment strategy.. There is substantial evidence for the efficacy of leptin (L) (neuroprotective hormone) and pioglitazone (P) (anti-inflammatory agent) as monotherapies in AD. We have previously shown that combination treatment of L+P in APP/PS1 mice at the onset of pathology significantly improved memory and reduced brain Aβ levels relative to control mice. In this new study, we sought to replicate our previous findings in a new cohort of APP/PS1 mice to further confirm whether the combined treatment of L+P is superior to each treatment individually.. We have re-evaluated the effects of L+P co-treatment in APP/PS1 mice using thioflavin-S staining, MOAβ immunolabeling, and enzyme-linked immunosorbent assay (ELISA) to examine effects on Aβ levels and pathology, relative to animals that received L or P individually.. We demonstrated that a combination of L and P significantly enhances the anti-Aβ effect of L or P in the hippocampus of APP/PS1 mice.. Our findings suggest that combining L and P significantly enhances the anti-Aβ effect of L or P in the hippocampus of APP/PS1 mice and maybe a potential new effective strategy for AD therapy.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Disease Models, Animal; Hippocampus; Humans; Hypoglycemic Agents; Leptin; Male; Memory; Mice; Mice, Transgenic; Pioglitazone

Animal studies provide strong evidence that the CNS directly regulates bone remodeling through the actions of the hypothalamus via two distinct pathways, the neural (mediated by leptin) arm and neurohumoral (mediated by neurohormones and growth factors) arm. The impact of AD on central regulatory mechanisms of bone mass is not known.. To test a model that assesses the relationship between hypothalamic atrophy and bone loss in Alzheimer's disease (AD) and potential mediation through neural (leptin) and neurohumoral (insulin-like growth factor -1, IGF-1) mechanisms.. AD-related hypothalamic structural change alters neural and neurohumoral regulatory systems of bone remodeling and contributes to bone loss in early AD.. A secondary data analysis of data obtained in a two-year longitudinal study with path analysis and longitudinal mediation modeling.. The data were collected as a part of the University of Kansas Brain Aging Project, a two-year observational study of 71 older adults with early stage AD and 69 non-demented controls.. Demographic characteristics and measures of bone density, body composition, and hypothalamic volume, serum levels of leptin, growth hormone, and IGF-1 were collected.. Hypothalamic atrophy and bone loss were observed in AD group and were associated. Data modeling suggests that bone loss may precede measurable changes in the brain. Leptin increased over two years in AD and the increase in leptin was associated with hypothalamic atrophy. However, changes in leptin or IGF-1 levels did not mediate the relationship between hypothalamic atrophy and bone loss.. This study extends previous findings by suggesting that bone loss in AD may be related to neurodegenerative changes (atrophy) in the hypothalamus. Further studies are needed to explore the role of brain atrophy and mediating mechanisms in bone loss. Further exploring temporal relationship between bone loss and AD may have an important diagnostic value.

Topics: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Animals; Atrophy; Body Composition; Bone Density; Bone Diseases, Metabolic; Brain; Case-Control Studies; Central Nervous System; Female; Human Growth Hormone; Humans; Hypothalamus; Insulin-Like Growth Factor I; Leptin; Life Style; Longitudinal Studies; Male; Models, Statistical

Adipose tissue dysfunction has been implicated in the pathophysiology of Alzheimer's disease. However, the involvement of adipokines, particularly adiponectin, remains unclear.. To compare serum and cerebrospinal fluid (CSF) levels of adiponectin, leptin and leptin-to-adiponectin ratio in patients within the spectrum of Alzheimer's disease and evaluate their relationship with classical biomarkers and their value as markers of progression.. Amnestic mild cognitive impairment (MCI, n = 71) and Alzheimer's dementia (AD, n = 53) subjects were consecutively recruited for serum and CSF adiponectin and leptin determination using an analytically validated commercial enzyme-linked immunosorbent assay (ELISA). Correlations were explored using adjusted Spearman's correlation coefficients. A logistic regression model and ROC analysis were performed to evaluate the staging predictive value of adipokines.. Serum adiponectin was 33% higher in AD when compared to MCI patients. Adiponectin CSF levels, similar in both groups, were positively correlated with Aβ42 and cognitive function, though only in women. The area under the ROC curve was 0.673 (95% CI:0.57-0.78) for serum adiponectin as predictor of dementia stage and the cut-off 10.85μg/ml maximized the sum of specificity (87%) and sensitivity (44%).. Although longitudinal studies are required, we hypothesize that higher serum adiponectin in AD patients constitutes a strategy to compensate possible central signaling defects. In addition, adiponectin might be specifically assigned to neuroprotective functions in women and eventually involved in the female-biased incidence of Alzheimer's disease.

Topics: Adipokines; Adiponectin; Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Cognitive Dysfunction; Cross-Sectional Studies; Enzyme-Linked Immunosorbent Assay; Female; Humans; Leptin; Longitudinal Studies; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Peptide Fragments; Sensitivity and Specificity; Sex Characteristics

Disruption of leptin signalling has been implicated as playing a role in the development of Alzheimer's disease (AD). Leptin has previously been shown to be affected by amyloid-beta (Aβ)-related signalling; however, pathways that link leptin to the disease pathogenesis have not been determined. To characterize the association between increasing age-dependent Aβ levels with leptin signalling and the vulnerable brain regions in AD, we assessed the mRNA and protein expression profile of leptin and leptin receptor (Ob-Rb) at 9 and 18-month-age in APP/PS1 mice. Immunohistochemical labelling demonstrated that leptin and Ob-Rb proteins were localised to neocortical and hippocampal neurons in APP/PS1 and wildtype (WT) mice. Neuronal leptin and Ob-Rb immunolabelling was more prominent in the neocortex of both groups at 9 month of age, while, at 18 months, labelling was reduced in the hippocampus of APP/PS1 mice relative to WT. Immunoblotting analysis demonstrated decreased hippocampal leptin levels, concomitantly with an increased Ob-Rb levels, in APP/PS1 mice compared with WT controls at 18 month of age. While no leptin mRNA was found in either of the groups analysed, Ob-Rb mRNA was significantly decreased in the hippocampus of APP/PS1 mice at both ages analysed. In addition, a significant decreased protein kinase B (Akt) activity concomitantly with an upregulation of suppressor of cytokine signaling-3 (SOCS3) and protein-tyrosine phosphatase 1B (PTP1B) transcripts was present. Thus, these results collectively indicate alterations of leptin signalling in the hippocampus of APP/PS1 mice, providing novel insights about the pathways that could link aberrant leptin signaling to the pathological changes of AD.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Disease Models, Animal; Hippocampus; Leptin; Mice; Mice, Transgenic; Neurons; Presenilin-1; Receptors, Leptin; Signal Transduction

Topics: Adipose Tissue, Brown; Alzheimer Disease; Animals; Blood Glucose; Diet, High-Fat; Disease Models, Animal; Eating; Homeostasis; Humans; Hyperphagia; Insulin; Insulin Resistance; Leptin; Metabolic Syndrome; Mice; Mice, Transgenic; Obesity

Cognitive impairment, including mild cognitive impairment (MCI) and dementia, compromises the patients' cognitive abilities and, to different extents, to carry out daily activities, accompanied by personality and behavioral changes. Studies suggest that leptin, an adipokine, has a neuroprotective role against Alzheimer's disease (AD) and that cytokines are associated with inflammatory processes and dementia. This study aimed to evaluate serum leptin, hsCRP, IL-6 and TNF-α levels in a cognitive continuum group from normal to demential status, and to assess whether they correlates to Mini-Mental State Examination (MMSE) and Functional Assessment Staging (FAST) scores. Forty-three participants were included, of whom 12 with probable AD, 18 with MCI and 13 with no objective cognitive decline. Serum leptin and hsCRP levels were evaluated by immunoturbidimetric method, and IL-6 and TNF-α by ELISA. Higher TNF-α levels were found in individuals with FAST stages 1/2 and normal scores evaluated by MMSE. hsCRP levels were inversely correlated with FAST stages. No association with function or global cognition was observed for leptin and IL-6 levels. However, women presented higher leptin serum levels than men while lower leptin and IL-6 levels were observed in individuals aged ≥59 years. Our results suggest that TNF-α is associated with cognitive and functional decline and that inflammation could be a substrate of cognitive impairment at early clinical stages of dementia.

Topics: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Biomarkers; C-Reactive Protein; Cognitive Dysfunction; Female; Humans; Interleukin-6; Leptin; Male; Middle Aged; Tumor Necrosis Factor-alpha

There is evidence that adipokines have roles in brain functioning and cognitive decline.. Assess the role of leptin and adiponectin levels in predicting changes in neuro-cognitive disorders (NCD).. The study included 205 patients over 65 years of age presenting for a one-day hospitalization for current assessment of cognitive function. Peripheral blood leptin and adiponectin levels were measured at admission. Demographic variables, body mass index (BMI), and history of hypertension were also recorded. Cognitive function was assessed by the Mini-Mental State Examination (MMSE) at admission and at later scheduled visits over a median follow-up period of 14.5 months. Conventional univariate comparisons were made between diagnosis groups (Alzheimer's disease (AD), mild NCD, vascular/mixed dementia). Changes in MMSE scores over time were examined with regard to the above variables using a linear mixed model.. The mean BMI was significantly lower (by 2 kg/m2, p = 0.01) in patients with AD than in patients with either mild-NCD or vascular/mixed dementia. Leptin levels were significantly higher (p = 0.043) and adiponectin levels significantly lower (p = 0.045) in patients with mild-NCD than in patients with major-NCD (AD or vascular/mixed dementia). However, the mixed model suggested no influence of the baseline levels of these two biomarkers on the course of cognitive decline.. The present study confirms the associations between leptin and adiponectin and AD or AD-related disorders but did not confirm that these peptides may be used as predictive biomarkers of cognitive decline.

Topics: Adiponectin; Aged; Aged, 80 and over; Alzheimer Disease; Body Mass Index; Cognitive Dysfunction; Dementia, Vascular; Female; Humans; Leptin; Male

The aim of the study was to determine the role of adiponectin, leptin and resistin in various types of dementia and to investigate their association with inflammatory markers, insulin resistance and abdominal obesity. In 205 patients with dementia [89 with Alzheimer's disease (AD), 47 with vascular dementia (VaD), 69 with mixed dementia (MD)], 113 persons with mild cognitive impairment and in 107 controls serum adiponectin, leptin and resistin levels, pro-inflammatory [interleukin-6 (IL-6), C-reactive protein (hsCRP) and chitotriosidase] and anti-inflammatory (25-OH vitamin D, HDL-cholesterol and paraoxonase 1) markers, as well as glucose metabolism parameters (glucose, insulin and HOMA-IR) were determined. In all-cause dementia adiponectin and resistin levels were significantly higher as compared to the controls; leptin levels did not show differences. Higher adiponectin levels concerned AD and MD, whereas higher resistin-VaD and MD. After stratification by abdominal obesity the differences in adiponectin levels remained significant in subjects without obesity. In all-cause dementia negative correlation of adiponectin with obesity, glucose metabolism parameters, IL-6 and hsCRP and positive correlation with HDL-cholesterol were found. Positive correlation of resistin with age, IL-6, hsCRP and chitotriosidase and negative correlation with HDL-cholesterol and paraoxonase 1 were stated. We conclude that dementia of neurodegenerative origin is characterized by elevated adiponectin levels, whereas dementia with vascular changes by increase of resistin. Association with inflammatory indicators may suggest the pro-inflammatory role of resistin in the development of dementia, especially in dementia of vascular mechanism. Identification of this novel biomarker may be important in preventing dementia.

Topics: Adiponectin; Aged; Aged, 80 and over; Alzheimer Disease; Biomarkers; Case-Control Studies; Cognitive Dysfunction; Dementia, Vascular; Female; Humans; Inflammation Mediators; Insulin Resistance; Leptin; Male; Obesity, Abdominal; Resistin; Up-Regulation

The coincidences between Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are so compelling that it is attractive to speculate that diabetic conditions might aggravate AD pathologies by calcium dysfunction, although the understanding of the molecular mechanisms involved remains elusive. The present work was undertaken to investigate whether calcium dyshomeostasis is associated with the exacerbated Alzheimer-like cognitive dysfunction observed in diabetic conditions in APP/PS1-ob/ob mice, which were generated by crossing ob/ob mice with APP/PS1 mice. We confirmed that the diabetic condition can aggravate not only Aβ deposition but also tau phosphorylation, synaptic loss, neuronal death, and inflammation, exacerbating cognitive impairment in AD mice. More importantly, we found that the diabetic condition dramatically elevated calcium levels in APP/PS1 mice, thereby stimulating the phosphorylation of the calcium-dependent kinases. Our findings suggest that controlling over-elevation of intracellular calcium may provide novel insights for approaching AD in diabetic patients and delaying AD progression.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Calcium Signaling; Cognitive Dysfunction; Diabetes Mellitus, Type 2; Disease Models, Animal; Humans; Inflammation; Leptin; Male; Memory Disorders; Mice; Mice, Transgenic; Phosphorylation; Protein Aggregation, Pathological; Signal Transduction; Synapses; tau Proteins

Metabolic syndrome and vascular dysfunction was suggested to be the risk factors for Alzheimer's disease (AD). Xuefu Zhuyu decoction (XZD) is a traditional Chinese medicine used to treat metabolic syndrome and cardiac-cerebral vascular disease. The effects of XZD on ameliorating metabolic syndrome, amyloid-related pathologies and cognitive impairment in an animal model of AD with metabolic stress was investigated.. The animal model of AD with metabolic stress was created by administrating high-fat diet and a low-dose injection of streptozotocin prior to the appearance of senile plaques in APP/PS1 transgenic mice. The diabesity-associated metabolic changes and AD-related pathological alterations were examined.. We found that XZD reduced body weight, insulin and leptin level, HOMA-IR, hepatic triglyceride, serum Aβ42 in the metabolic stressed AD animal. XZD also ameliorated oral glucose tolerant, Aβ deposition, astrocyte and microglia activation in the vicinity of plaques, and nesting behavior in the metabolic stressed AD animal.. The results of this study suggest that XZD is able to reduce the peripheral metabolic stress-mediated vascular hypoperfusion, neuroinflammation and AD-related pathology in APP/PS1 mice.

Topics: Alzheimer Disease; Amyloid; Amyloid beta-Protein Precursor; Animals; Blood Glucose; Cognitive Dysfunction; Drugs, Chinese Herbal; Fatty Liver; Homeostasis; Inflammation; Insulin; Insulin Resistance; Leptin; Male; Mice; Mice, Transgenic; Obesity; Stress, Physiological; Triglycerides

A key pathology of Alzheimer's disease (AD) is amyloid β (Aβ) accumulation that triggers synaptic impairments and neuronal death. Metabolic disruption is common in AD and recent evidence implicates impaired leptin function in AD. Thus the leptin system may be a novel therapeutic target in AD. Indeed, leptin has cognitive enhancing properties and it prevents the aberrant effects of Aβ on hippocampal synaptic function and neuronal viability. However, as leptin is a large peptide, development of smaller leptin-mimetics may be the best therapeutic approach. Thus, we have examined the cognitive enhancing and neuroprotective properties of known bioactive leptin fragments. Here we show that the leptin (116-130) fragment, but not leptin (22-56), mirrored the ability of leptin to promote AMPA receptor trafficking to synapses and facilitate activity-dependent hippocampal synaptic plasticity. Administration of leptin (116-130) also mirrored the cognitive enhancing effects of leptin as it enhanced performance in episodic-like memory tests. Moreover, leptin (116-130) prevented hippocampal synaptic disruption and neuronal cell death in models of amyloid toxicity. These findings establish further the importance of the leptin system as a therapeutic target in AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Cell Death; Cognition; Hippocampus; Humans; Leptin; Memory; Neuronal Plasticity; Neurons; Peptide Fragments; Synapses

Over the last few decades, there has been a significant increase in epidemiological studies suggesting that type 2 diabetes (T2DM) is linked to a higher risk of Alzheimer's disease (AD). However, how T2DM affects AD pathology, such as tau hyperphosphorylation, is not well understood. In this study, we investigated the impact of T2DM on tau phosphorylation in ob/ob mice, a spontaneous genetic model of T2DM. Tau phosphorylation at the AT8 epitope was slightly elevated in 4-week-old ob/ob mice while 26-week-old ob/ob mice exhibited tau hyperphosphorylation at multiple tau phospho-epitopes (Tau1, CP13, AT8, AT180, PHF1). We then examined the mechanism of tau hyperphosphorylation and demonstrated that it is mostly due to hypothermia, as ob/ob mice were hypothermic and normothermia restored tau phosphorylation to control levels. As caffeine has been shown to be beneficial for diabetes, obesity and tau phosphorylation, we, therefore, used it as therapeutic treatment. Unexpectedly, chronic caffeine intake exacerbated tau hyperphosphorylation by promoting deeper hypothermia. Our data indicate that tau hyperphosphorylation is predominately due to hypothermia consequent to impaired thermoregulation in ob/ob mice. This study establishes a novel link between diabetes and AD, and reinforces the importance of recording body temperature to better assess the relationship between diabetes and AD.

Topics: Alzheimer Disease; Animals; Body Temperature; Body Temperature Regulation; Caffeine; Central Nervous System Stimulants; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Hippocampus; Hypothermia; Leptin; Male; Mice, Inbred C57BL; Mice, Mutant Strains; Phosphorylation; tau Proteins

Low plasma leptin levels can be a risk factor for Alzheimer's disease (AD) but the relation of leptin with disease progression in clinical AD is unknown.. The aim of this study was to investigate the relation between serum leptin concentrations and cognitive decline in clinical AD.. Serum leptin levels were analyzed in 295 non-obese subjects including healthy controls (n = 65), patients with subjective memory complaints (n = 99), patients with AD (n = 100), and patients with vascular dementia (n = 31). Leptin levels were related to hippocampal atrophy, baseline Mini-Mental State Examination (MMSE) scores and annual decline in MMSE measured over 2 years (range 0.4-4.5 years).. Serum leptin levels were similar in AD patients compared to healthy controls and patients with subjective memory complaints. No correlation was observed between leptin concentrations and MMSE, annual change in MMSE during follow-up or atrophy.. Serum leptin levels are not altered in this population of relatively young AD or vascular dementia patients (mean 60) compared to healthy and clinical control groups and were not related to cognitive decline. These results suggest that peripheral leptin levels do not play a role in evolution of AD pathology.

Topics: Aged; Alzheimer Disease; Body Mass Index; Cognition Disorders; Female; Humans; Leptin; Magnetic Resonance Imaging; Male; Mental Status Schedule; Middle Aged; Sex Factors

Several studies support the relation between leptin and Alzheimer's disease (AD). We show that leptin levels in CSF are unchanged as subjects progress to AD. However, in AD hippocampus, leptin signalling was decreased and leptin localization was shifted, being more abundant in reactive astrocytes and less in neurons. Similar translocation of leptin was found in brains from Tg2576 and apoE4 mice. Moreover, an enhancement of leptin receptors was found in hippocampus of young Tg2576 mice and in primary astrocytes and neurons treated with Aβ₁₋₄₂. In contrast, old Tg2576 mice showed decreased leptin receptors levels. Similar findings to those seen in Tg2576 mice were found in apoE4, but not in apoE3 mice. These results suggest that leptin levels are intact, but leptin signalling is impaired in AD. Thus, Aβ accumulation and apoE4 genotype result in a transient enhancement of leptin signalling that might lead to a leptin resistance state over time.

Topics: Aged; Alzheimer Disease; Animals; Apolipoprotein E4; Biomarkers; Brain; Cohort Studies; Female; Hippocampus; Humans; Leptin; Linear Models; Male; Mice, Inbred C57BL; Mice, Transgenic; Neuroimaging; Organ Size; Receptors, Leptin; Signal Transduction

Millions of Mexico, US and across the world children are overweight and obese. Exposure to fossil-fuel combustion sources increases the risk for obesity and diabetes, while long-term exposure to fine particulate matter (PM2.5) and ozone (O3) above US EPA standards is associated with increased risk of Alzheimer's disease (AD). Mexico City Metropolitan Area children are chronically exposed to PM2.5 and O3 concentrations above the standards and exhibit systemic, brain and intrathecal inflammation, cognitive deficits, and Alzheimer disease neuropathology. We investigated adipokines, food reward hormones, endothelial dysfunction, vitamin D and apolipoprotein E (APOE) relationships in 80 healthy, normal weight 11.1±3.2 year olds matched by age, gender, BMI and SES, low (n: 26) versus high (n:54) PM2.5 exposures. Mexico City children had higher leptin and endothelin-1 (p<0.01 and p<0.000), and decreases in glucagon-like peptide-1 (GLP 1), ghrelin, and glucagon (<0.02) versus controls. BMI and leptin relationships were significantly different in low versus high PM2.5 exposed children. Mexico City APOE 4 versus 3 children had higher glucose (p=0.009). Serum 25-hydroxyvitamin D<30 ng/mL was documented in 87% of Mexico City children. Leptin is strongly positively associated to PM 2.5 cumulative exposures. Residing in a high PM2.5 and O3 environment is associated with 12h fasting hyperleptinemia, altered appetite-regulating peptides, vitamin D deficiency, and increases in ET-1 in clinically healthy children. These changes could signal the future trajectory of urban children towards the development of insulin resistance, obesity, type II diabetes, premature cardiovascular disease, addiction-like behavior, cognitive impairment and Alzheimer's disease. Increased efforts should be made to decrease pediatric PM2.5 exposures, to deliver health interventions prior to the development of obesity and to identify and mitigate environmental factors influencing obesity and Alzheimer disease.

Topics: Adolescent; Alzheimer Disease; Body Weight; Case-Control Studies; Child; Cohort Studies; Endothelin-1; Hormones; Humans; Leptin; Mexico; Obesity; Particulate Matter; Vitamin D Deficiency

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by irreversible and progressive loss of memory and other cognitive functions. Controversies still exist on the precise mechanisms contributing to neurodegeneration. Obesity and disturbances in metabolic homeostasis are thought to be AD risk factors. Adipokine leptin has receptors in the brain, also in the regions related to AD. Leptin may protect against AD. The aim was to assess leptin and soluble leptin receptor levels in plasma as well as free leptin index (FLI) in correlation with metabolic status of women diagnosed with Alzheimer's disease. Eighteen women with moderate to severe stage of AD, 40 women with AD at early stage, and 42 female controls, matched for age and body mass index, participated in the study. Leptin and soluble leptin receptor levels were measured with RIA and IRMA, respectively. Then, FLI was calculated. In addition, metabolic parameters (lipid profile, glucose and insulin concentrations, HOMA-IR) were estimated. Clinical and anthropometric data were collected. The Mini-Mental State Examination (MMSE) as a cognitive impairment measurement was performed. Correlations with both leptin and FLI, and MMSE, clinical and biochemical parameters were evaluated. Leptin levels and FLI were significantly lower and leptin receptor concentrations were higher in AD subjects when compared with the controls. In AD group leptin, soluble leptin receptor and FLI correlated with selected metabolic parameters but not with MMSE. We conclude that alterations in leptin, leptin receptor, and FLI were the most intensified in advanced AD. However, these results did not correlate with dementia stage measured with MMSE. Therefore, further intensive research is needed to explain the mechanisms involved in this phenomenon.

Topics: Aged; Alzheimer Disease; Body Mass Index; Female; Humans; Leptin; Mental Status Schedule; Receptors, Leptin

Total and central adiposity have been associated with increased risk of Alzheimer's disease (AD). Visceral and subcutaneous adipose tissues have different metabolic characteristics and could therefore be differentially associated with AD.. To compare regional fat distribution determined by magnetic resonance imaging (MRI) in AD patients and healthy controls and investigate associations with stage of the disease and chemical markers. The investigation was performed in a prospective case-control study.. We examined thirty patients with mild to moderate AD by whole-body MRI (1.5 T) and clinical questionnaires in comparison to thirty cognitively healthy age- and gender-matched study participants. Volumes of total, subcutaneous, and visceral body fat tissue were determined by an unbiased automatic analysis algorithm. Levels of leptin, ghrelin, and adiponectin were determined in serum, amyloid-β (Aβ)(1-42) and tau protein levels in cerebrospinal fluid (CSF).. Male AD patients displayed significantly more total fat tissue than male controls. This difference was not observed in women. We observed a trend toward higher volume of visceral fat tissue in all patients (p = 0.13). Severity of disease was not associated with fat distribution in our study. Increased leptin levels correlated with lower CSF Aβ(1-42) in female, but not in male, AD patients.. Fat volume is increased in male, but not in female AD patients. Negative correlation of leptin levels and CSF Aβ(1-42) in females might be one co-factor for the increased AD risk of females. Further studies are required to confirm this gender difference in fat volume during AD and evaluate its pathophysiological importance.

Topics: Adipose Tissue; Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Body Fat Distribution; Case-Control Studies; Enzyme-Linked Immunosorbent Assay; Female; Humans; Image Processing, Computer-Assisted; Leptin; Magnetic Resonance Imaging; Male; Middle Aged; Pattern Recognition, Automated; Peptide Fragments; Prospective Studies; Severity of Illness Index; Sex Characteristics; Whole Body Imaging

We have previously demonstrated that geniposide attenuates the production of Aβ1-42 both in vitro and in vivo via enhancing leptin receptor signaling. But the role played by geniposide in the phosphorylation of tau and its underlying molecular mechanisms remain unclear. In this study, we investigated the effect of geniposide on the phosphorylation of tau and the role of leptin signaling in this process. Our data suggested that, accompanied by the up-regulation of leptin receptor expression, geniposide significantly decreased the phosphorylation of tau in rat primary cultured cortical neurons and in APP/PS1 transgenic mice, and this geniposide-induced decrease of tau phosphorylation could be prevented by leptin antagonist (LA). Furthermore, LA also prevented the phosphorylation of Akt at Ser-473 site and GSK-3β at Ser-9 site induced by geniposide. All these results indicate that geniposide may regulate tau phosphorylation through leptin signaling, and geniposide may be a promising therapeutic compound for the treatment of Alzheimer's disease in the future.

Topics: Alzheimer Disease; Animals; Gene Expression Regulation; Glycogen Synthase Kinase 3 beta; Iridoids; Leptin; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurons; Phosphorylation; Rats; Receptors, Leptin; Signal Transduction; tau Proteins

Brain aging is accompanied by alternations of brain structure, functions and the cognitive impairment. With respect to cognitive decline, the elderly population is far from homogeneous, as well as heterogeneous, which presents successful aging, normal aging, mild cognitive impairment and Alzheimer's disease. Studies demonstrated that higher serum leptin levels are associated with normal cognition in older adults without significant neurological conditions, while it is lower in most mild cognitive impairment patients. Leptin can improve cognitive disorders and referred to as a potential cognitive enhancer. Therefore, low level of leptin plays an significant role in cognitive impairment development in elderly people.

Topics: Aging; Alzheimer Disease; Brain; Cognition; Cognitive Dysfunction; Humans; Learning; Leptin

Leptin signaling has received considerable attention in the Alzheimer disease (AD) field. Within the past decade, the peptide hormone has been demonstrated to attenuate tau hyperphosphorylation in neuronal cells and to be modulated by amyloid-β. Moreover, a role in neuroprotection and neurogenesis within the hippocampus has been shown in animal models. To further characterize the association between leptin signaling and vulnerable regions in AD, we assessed the profile of leptin and the leptin receptor in AD and control patients. We analyzed leptin levels in CSF, and the concentration and localization of leptin and leptin receptor in the hippocampus. Significant elevations in leptin levels in both CSF and hippocampal tissue of AD patients, compared with age-matched control cases, indicate a physiological up-regulation of leptin in AD. However, the level of leptin receptor mRNA decreased in AD brain and the leptin receptor protein was localized to neurofibrillary tangles, suggesting a severe discontinuity in the leptin signaling pathway. Collectively, our results suggest that leptin resistance in the hippocampus may play a role in the characteristic changes associated with the disease. These findings are the first to demonstrate such dysregulated leptin-signaling circuitry and provide novel insights into the possible role of aberrant leptin signaling in AD. In this study, increased leptin was found in CSF and hippocampus in Alzheimer disease indicating its physiological up-regulation, yet leptin receptor mRNA was decreased and leptin receptor protein was localized to neurofibrillary tangles, suggesting a discontinuity in the leptin signaling pathway. The lack of leptin signaling within degenerating neurons may represent a novel neuronal leptin resistance in Alzheimer disease.

Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Down-Regulation; Female; Hippocampus; Humans; Leptin; Male; Middle Aged; Neurofibrillary Tangles; Neurons; Protein Binding; Receptors, Leptin; Signal Transduction; Young Adult

Analysis of data derived from the Alzheimer's Disease Neuroimaging Initiative (ADNI) program showed plasma leptin levels in individuals with Mild Cognitive Impairment (MCI) or Alzheimer's disease (AD) to be lower than those of subjects with normal cognition (NC). Approximately 70% of both men and women with MCI have plasma leptin levels lower than the median values of NC. Additionally, half of these subjects carry at least one apolipoprotein-E4 (APOE-ε4) allele. A subgroup of participants also had cerebrospinal fluid (CSF) leptin measured. Plasma leptin typically reflected the levels of leptin in CSF in all groups (Control/MCI/AD) in both genders. The data suggest that plasma leptin deficiency provides an indication of potential CNS leptin deficiency, further supporting the exploration of plasma leptin as a diagnostic marker for MCI or AD. The important question is whether leptin deficiency plays a role in the causation of AD and/or its progression. If this is the case, individuals with early AD or MCI with low plasma leptin may benefit from leptin replacement therapy. Thus, these data indicate that trials of leptin in low leptin MCI/early-stage AD patients should be conducted to test the hypothesis.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Biomarkers; Cognitive Dysfunction; Databases, Factual; Disease Progression; Female; Humans; Leptin; Male; Sex Characteristics

To investigate whether patients with behavioral variant frontotemporal dementia (bvFTD) have dysregulation in satiety-related hormonal signaling using a laboratory-based case-control study.. Fifty-four participants (19 patients with bvFTD, 17 patients with Alzheimer disease dementia, and 18 healthy normal controls [NCs]) were recruited from a tertiary-care dementia clinic. During a standardized breakfast, blood was drawn before, during, and after the breakfast protocol to quantify levels of peripheral satiety-related hormones (ghrelin, cortisol, insulin, leptin, and peptide YY) and glucose. To further explore the role of patients' feeding abnormalities on hormone levels, patients were classified into overeating and nonovereating subgroups based on feeding behavior during separate laboratory-based standardized lunch feeding sessions.. Irrespective of their feeding behavior in the laboratory, patients with bvFTD, but not patients with Alzheimer disease dementia, have significantly lower levels of ghrelin and cortisol and higher levels of insulin compared with NCs. Furthermore, while laboratory feeding behavior did not predict alterations in levels of ghrelin, cortisol, and insulin, only patients with bvFTD who significantly overate in the laboratory demonstrated significantly higher levels of leptin compared with NCs, suggesting that leptin may be sensitive to particularly severe feeding abnormalities in bvFTD.. Despite a tendency to overeat, patients with bvFTD have a hormonal profile that should decrease food intake. Aberrant hormone levels may represent a compensatory response to the behavioral or neuroanatomical abnormalities of bvFTD.

Topics: Aged; Alzheimer Disease; Biomarkers; Blood Glucose; Case-Control Studies; Feeding Behavior; Female; Frontotemporal Dementia; Ghrelin; Humans; Hydrocortisone; Hyperphagia; Insulin; Leptin; Male; Middle Aged; Neuropsychological Tests; Peptide YY

There is growing evidence that leptin is able to ameliorate Alzheimer's disease (AD)-like pathologies, including brain amyloid-β (Aβ) burden. In order to improve the therapeutic potential for AD, we generated a lentivirus vector expressing leptin protein in a self-inactivating HIV-1 vector (HIV-leptin), and delivered this by intra-cerebroventricular administration to APP/PS1 transgenic model of AD. Three months after intra-cerebroventricular administration of HIV-leptin, brain Aβ accumulation was reduced. By electron microscopy, we found that APP/PS1 mice exhibited deficits in synaptic density, which were partially rescued by HIV-leptin treatment. Synaptic deficits in APP/PS1 mice correlated with an enhancement of caspase-3 expression, and a reduction in synaptophysin levels in synaptosome preparations. Notably, HIV-leptin therapy reverted these dysfunctions. Moreover, leptin modulated neurite outgrowth in primary neuronal cultures, and rescued them from Aβ42-induced toxicity. All the above changes suggest that leptin may affect multiple aspects of the synaptic status, and correlate with behavioral improvements. Our data suggest that leptin gene delivery has a therapeutic potential for Aβ-targeted treatment of mouse model of AD.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Caspase 3; Genetic Therapy; Genetic Vectors; HIV-1; Injections, Intraventricular; Leptin; Memory Disorders; Mice; Neurons; Presenilin-1; Synapses; Synaptophysin

Type 2 diabetes (T2D) is a major risk factor for late-onset Alzheimer's disease (AD). A variety of metabolic changes related to T2D (e.g. hyperinsulinemia, hyperglycemia, and elevated branched-chain amino acids) have been proposed as mechanistic links, but the basis for this association remains unknown. Retromer-dependent trafficking is implicated in the pathogenesis of AD, and two key retromer proteins, VPS35 and VPS26, are deficient in the hippocampal formation of AD patients. We characterized VPS35 levels in five different mouse models of T2D/obesity to identify specific metabolic factors that could affect retromer levels in the brain. Mouse models in which hyperleucinemia was present displayed hippocampus-selective retromer deficiency. Wild-type lean mice fed a high leucine diet also developed hippocampal-selective retromer deficiency, and neuronal-like cells grown in high ambient leucine had reduced retromer complex proteins. Our results suggest that hyperleucinemia may account, in part, for the association of insulin resistance/T2D with AD.

Topics: Alzheimer Disease; Analysis of Variance; Animals; Cell Line, Tumor; Diabetes Mellitus, Type 2; Disease Progression; Enzyme-Linked Immunosorbent Assay; Glucose Tolerance Test; Hippocampus; Humans; Leptin; Leucine; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neuroblastoma; Vesicular Transport Proteins

Cerebral hypometabolism of glucose, weight loss, and decreased food intake are characteristic features of sporadic Alzheimer's disease (AD). A systematic study on the serum levels of adipokines and insulin, the major hormones regulating energy metabolism, food intake, and body weight, in sporadic AD is necessary. The present study compares the serum levels of leptin, adiponectin, and insulin, measured by commercially available immuno-assay kits, between controls and sporadic AD subjects. The results show a conspicuous decrease in the level of leptin, a dramatic rise in the level of adiponectin, and also a statistically significant increase in insulin level, in the blood of AD subjects, with respect to controls. The changes in the serum levels of adiponectin and insulin in AD are positively correlated with the severity of dementia. Likewise, the serum level of leptin in AD subjects is negatively correlated with the degree of dementia. The changes in the levels of adipokines and insulin have implications in the amyloid pathology, neurodegeneration, and hypometabolism of glucose existing in the AD brain.

Topics: Adiponectin; Aged; Alzheimer Disease; Blood Chemical Analysis; Female; Humans; Immunoassay; Insulin; Leptin; Male; Middle Aged; Psychiatric Status Rating Scales

Weight loss is a prominent early feature of Alzheimer's disease (AD) that often precedes the cognitive decline and clinical diagnosis. While the exact pathogenesis of AD remains unclear, accumulation of amyloid-β (Aβ) derived from the amyloid precursor protein (APP) in the brain is thought to lead to the neuronal dysfunction and death underlying the dementia. In this study, we examined whether transgenic mice overexpressing the Swedish mutation of APP (Tg2576), recapitulating selected features of AD, have hypothalamic leptin signaling dysfunction leading to early body weight deficits. We found that 3-month-old Tg2576 mice, before amyloid plaque formation, exhibit decreased weight with markedly decreased adiposity, low plasma leptin levels, and increased energy expenditure without alterations in feeding behavior. The expression of the orexigenic neuropeptide Y (NPY) in the hypothalamus to the low leptin state was abnormal at basal and fasting conditions. In addition, arcuate NPY neurons exhibited abnormal electrophysiological responses to leptin in Tg2576 hypothalamic slices or wild-type slices treated with Aβ. Finally, the metabolic deficits worsened as Tg2576 mice aged and amyloid burden increased in the brain. These results indicate that excess Aβ can potentially disrupt hypothalamic arcuate NPY neurons leading to weight loss and a pathologically low leptin state early in the disease process that progressively worsens as the amyloid burden increases. Collectively, these findings suggest that weight loss is an intrinsic pathological feature of Aβ accumulation and identify hypothalamic leptin signaling as a previously unrecognized pathogenic site of action for Aβ.

Topics: Adiposity; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Arcuate Nucleus of Hypothalamus; Brain; Brain Chemistry; Disease Models, Animal; Disease Progression; Fasting; Feeding Behavior; Female; Genes, Reporter; Humans; Hypothalamus; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Neurons; Neuropeptide Y; Patch-Clamp Techniques; Plaque, Amyloid; Weight Loss

It was recently established that the stomach-derived ghrelin and the adipokine leptin promote learning and memory through actions within the hippocampus. Changes in the peripheral or brain levels of these peptides were described in Alzheimer's disease (AD) patients and were shown to correlate with the severity of cognitive decline. Furthermore, in vivo and in vitro studies demonstrated that leptin or ghrelin can ameliorate amyloid and tau pathologies as well as cognitive deficits. However, the exact role of these peptides in AD is far from being elucidated. To fill this gap, our working hypothesis was that leptin and ghrelin can exert a neuroprotective role in AD suppressing hippocampal dysfunction triggered by synapto- and neurotoxic amyloid-β oligomers (AβO). Using primary cultured hippocampal neurons, we demonstrated that both peptides reduce AβO-induced production of superoxide and mitochondrial membrane depolarization, improving cell survival, and inhibit cell death through a receptor-dependent mechanism. Furthermore, it was shown that in AβO-treated neurons both leptin and ghrelin prevent glycogen synthase kinase 3β activation. Therefore, the evidence gathered in this study revealed that leptin and ghrelin can act as neuroprotective agents able to rescue hippocampal neurons from AβO toxicity, thus highlighting their potential therapeutic role in AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Blotting, Western; Cell Survival; Cells, Cultured; Ghrelin; Hippocampus; Leptin; Neurons; Peptide Fragments; Protein Multimerization; Rats; Rats, Wistar

Topics: Aged; Aging; Alzheimer Disease; Animals; Brain; Caloric Restriction; Cognition; Cognition Disorders; Eating; Energy Intake; Humans; Leptin; Mitochondria; Nutritional Status

Leptin, a hormone produced by body fat tissue, acts on hypothalamic receptors in the brain to regulate appetite and energy expenditure, and on neurons in the arcuate nucleus to signal that an individual has had enough to eat. Leptin enters the central nervous system at levels that depend on an individual's body fat. Obese people, on average, show greater brain atrophy in old age, so it is valuable to know whether brain atrophy relates to leptin levels, which can be targeted by interventions. We therefore determined how plasma leptin levels, and BMI, relate to brain structure, and whether leptin levels might account for BMI's effect on the brain. We measured regional brain volumes using tensor-based morphometry, in MRI scans of 517 elderly individuals with plasma leptin measured (mean: 13.3±0.6 ng/ml; mean age: 75.2±7.3 years; 321 men/196 women). We related plasma leptin levels to brain volumes at every location in the brain after adjusting for age, sex, and diagnosis and, later, also BMI. Plasma leptin levels were significantly higher (a) in women than men, and (b) in obese versus overweight, normal or underweight individuals. People with higher leptin levels showed deficits in frontal, parietal, temporal and occipital lobes, brainstem, and the cerebellum, irrespective of age, sex, or diagnosis. These associations persisted after controlling for BMI. Greater brain atrophy may occur in people with central leptin insufficiency, a marker of obesity. Therapeutic manipulation of leptin may be a promising direction for slowing brain decline.

Topics: Adipose Tissue; Age Factors; Aged; Aged, 80 and over; Alzheimer Disease; Body Mass Index; Brain; Energy Metabolism; Hormones; Humans; Leptin; Middle Aged; Neuroimaging; Obesity; Sex Factors

To examine and compare the pleiotropic effects on oxidative stress and metabolic signaling pathways of atorvastatin and pitavastatin in mouse model of Alzheimer's disease (AD).. We gave the transgenic (Tg) mice either atorvastatin or pitavastatin from 5-20 months (M) of age, and performed immunohistological analysis [4-hydroxy-2-nonenal (4-HNE)-positive, advanced glycation end products (AGEs), low-density lipoprotein receptor (LDL-R)-positive neurons, apolipoprotein E (ApoE)-positive senile plaque (SP), and insulin receptor (IR)-positive endothelium], and biochemistry analysis (adiponectin and leptin).. The numbers of 4-HNE- and AGE-positive neurons and the sum of ApoE-positive SP size progressively increased with age in amyloid precursor protein (APP)-Tg mice, while the amount of IR-positive endothelium and the number of LDL-R-positive neurons decreased. Adiponectin and leptin serum levels were lower in APP-Tg mice than in non-Tg mice. Treatment with statins reduced the number of AGE-positive neurons from as early as 10 M, preserved the numbers of 4-HNE- and LDL-R-positive neurons and the amount of IR-positive endothelium at 15 M, and reduced the sum of ApoE-positive SP size and adiponectin serum level at 20 M.. Atorvastatin and pitavastatin reduced the level of oxidative stress, as revealed by the presence of 4-HNE and AGE, in AD mouse brains, and that treatment with statins improves insulin signaling and LDL-R/ApoE systems. The beneficial effects of these statins may be associated with direct pleiotropic effects on AD mouse brains, indirect effects through improving the serum adiponectin/leptin balance, or both.

Topics: Adiponectin; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Atorvastatin; Cerebral Cortex; Endothelium, Vascular; Female; Glycation End Products, Advanced; Heptanoic Acids; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Leptin; Mice; Neurons; Oxidative Stress; Plaque, Amyloid; Pyrroles; Quinolines; Receptor, Insulin; Receptors, LDL

Epidemiological studies have suggested an inverse relationship between the adipocytokine leptin and the onset of Alzheimer's disease (AD), and leptin supplementation decreases amyloid-β (Aβ) production and tau phosphorylation (p-tau), two major biochemical events that play a key role in the pathogenesis of AD. We have previously shown that the cholesterol oxidized product 27-hydroxycholesterol (27-OHC) inhibits leptin expression, an effect that correlated with increased levels of Aβ and p-tau. We have also shown that 27-OHC induces endoplasmic reticulum (ER) stress, a cellular response that is implicated in AD and confers leptin resistance. However the extent to which ER stress is involved in 27-OHC-induced attenuation in leptin expression has not been determined. In this study we determined the involvement of ER stress in the 27-OHC-induced attenuation of leptin expression in SH-SY5Y human neuroblastoma cells. We demonstrate that 27-OHC-induced ER stress attenuates leptin expression by activating C/EBP Homologous Protein (CHOP) which negatively regulates C/EBPα, a transcription factor required for leptin expression. The molecular chaperone 4-phenylbutyric acid (4-PBA) precludes 27-OHC-evoked ER stress and down-regulation of leptin. Furthermore, we demonstrate that the activation of the transcription factor CHOP in response to ER stress is pivotal in the attenuation of leptin expression as knocking-down CHOP alleviates the attenuation in leptin expression. Our study implicates ER stress as the mechanistic link in the 27-OHC-induced negative regulation of leptin, a hormone that has potential therapeutic effects in AD by reducing Aβ and phosphorylated tau accumulation.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Cell Line, Tumor; Electrophoretic Mobility Shift Assay; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Gene Expression Regulation; Humans; Hydroxycholesterols; Leptin; Neuroblastoma; Phosphorylation; Real-Time Polymerase Chain Reaction; RNA, Small Interfering; Signal Transduction; tau Proteins; Transcription Factor CHOP

Diabetes increases the risk of Alzheimer's disease (AD). The pathological hallmarks for AD brains are extracellular amyloid plaques formed by β-amyloid peptide (Aβ) and intracellular neurofibrillary tangles consisting of hyperphosphorylated tau protein. This study was designed to determine AD-like brain changes in mice modeling for type 2 diabetes. The effects of metformin on these changes also were studied. Seven-week old male db/db mice received intraperitoneal injection of 200 mg kg⁻¹ d⁻¹ metformin for 18 weeks. They were subjected to Barnes maze at an age of 21 weeks and fear conditioning at an age of 24 weeks to assess their cognitive functions. Hippocampus was harvested after these tests for biochemical evaluation. The db/db mice had more tau phosphorylated at S396 and total tau in their hippocampi than their non-diabetic control db+mice. Activated/phosphorylated c-jun N-terminal kinase (JNK), a tau kinase, was increased in the db/db mouse hippocampus. Metformin attenuated the increase of total tau, phospho-tau and activated JNK. The db/db mice had increased Aβ levels. Metformin attenuated the reduction of synaptophysin, a synaptic protein, in the db/db mouse hippocampus. Metformin did not attenuate the impairments of spatial learning and memory as well as long-term hyperglycemia in the db/db mice. Our results suggest that the db/db mice have multiple AD-like brain changes including impaired cognitive functions, increased phospho-tau and Aβ as well as decreased synaptic proteins. Activation of JNK may contribute to the increased phospho-tau in the db/db mice. Metformin attenuates AD-like biochemical changes in the brain of these mice.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Conditioning, Psychological; Diabetes Mellitus, Type 2; Disease Models, Animal; Drug Resistance; Fear; Hippocampus; Hypoglycemic Agents; JNK Mitogen-Activated Protein Kinases; Leptin; Male; Maze Learning; Memory; Metformin; Mice; Mice, Obese; Neurofibrillary Tangles; Phosphorylation; Plaque, Amyloid; Protein Phosphatase 2; Synaptophysin; tau Proteins; Vesicular Transport Proteins

Weight loss is a characteristic finding of patients with Alzheimer's disease (AD). It seems that precedes cognitive impairment by some years, but the underlying causes are not fully understood. Ghrelin and leptin are involved in energy homeostasis, and may be implicated in weight losing observed in these patients.. To examine the potential relationship between ghrelin and leptin levels and weight loss in patients with AD.. The study included 27 patients (10 men and 17 women) with AD of moderate severity, and 23 controls (10 males and 13 females), matched for age and BMI. Body fat and lean mass content were assessed using a portable apparatus. Cognitive function was assessed with the Mini-Mental State Examination. Basal serum samples for the measurement of leptin, ghrelin, insulin and glucose were obtained, and serum ghrelin, insulin and glucose were measured after a 75-gr glucose load in both groups.. Patients with Alzheimer Disease (AD) have lower lean mass content compared to controls. Basal ghrelin and leptin is similar in patients with AD and controls. The area-under-the-curve for ghrelin (AUC) is lower in male patients with AD compared to control males, while no difference was observed between females AD and controls.. Male patients with AD, in contrast with female patients, fail to maintain a normal energy homeostasis even in the early stages of the disease, as shown by the decreased lean mass content in males AD compared to controls. Disruption of the normal compensatory modulation of ghrelin secretion might contribute to the metabolic changes observed in male patients with AD.

Topics: Aged; Alzheimer Disease; Area Under Curve; Body Composition; Body Fluid Compartments; Body Mass Index; Case-Control Studies; Cognition Disorders; Energy Metabolism; Female; Ghrelin; Humans; Leptin; Male; Middle Aged; Severity of Illness Index; Sex Factors; Weight Loss

We previously demonstrated that animals fed a high-fat (HF) diet for 10 weeks developed insulin resistance and behavioural inflexibility. We hypothesised that intervention with metformin would diminish the HF-feeding-evoked cognitive deficit by improving insulin sensitivity.. Rats were trained in an operant-based matching and non-matching to position task (MTP/NMTP). Animals received an HF (45% of kJ as lard; n = 24), standard chow (SC; n = 16), HF + metformin (144 mg/kg in diet; n = 20) or SC + metformin (144 mg/kg in diet; n = 16) diet for 10 weeks before retesting. Body weight and plasma glucose, insulin and leptin were measured. Protein lysates from various brain areas were analysed for alterations in intracellular signalling or production of synaptic proteins.. HF-fed animals developed insulin resistance and an impairment in switching task contingency from matching to non-matching paradigm. Metformin attenuated the insulin resistance and weight gain associated with HF feeding, but had no effect on performance in either MTP or NMTP tasks. No major alteration in proteins associated with insulin signalling or synaptic function was detected in response to HF diet in the hypothalamus, hippocampus, striatum or cortex.. Metformin prevented the metabolic but not cognitive alterations associated with HF feeding. The HF diet protocol did not change basal insulin signalling in the brain, suggesting that the brain did not develop insulin resistance. These findings indicate that HF diet has deleterious effects on neuronal function over and above those related to insulin resistance and suggest that weight loss may not be sufficient to reverse some damaging effects of poor diet.

Topics: Alzheimer Disease; Animals; Behavior, Animal; Body Weight; Brain; Cognition Disorders; Conditioning, Operant; Dietary Fats; Disease Models, Animal; Hormones; Hypoglycemic Agents; Insulin Resistance; Leptin; Male; Metformin; Nerve Tissue Proteins; Rats; Rats, Wistar; Signal Transduction; Treatment Failure

Complex diseases result from molecular changes induced by multiple genetic factors and the environment. To derive a systems view of how genetic loci interact in the context of tissue-specific molecular networks, we constructed an F2 intercross comprised of >500 mice from diabetes-resistant (B6) and diabetes-susceptible (BTBR) mouse strains made genetically obese by the Leptin(ob/ob) mutation (Lep(ob)). High-density genotypes, diabetes-related clinical traits, and whole-transcriptome expression profiling in five tissues (white adipose, liver, pancreatic islets, hypothalamus, and gastrocnemius muscle) were determined for all mice. We performed an integrative analysis to investigate the inter-relationship among genetic factors, expression traits, and plasma insulin, a hallmark diabetes trait. Among five tissues under study, there are extensive protein-protein interactions between genes responding to different loci in adipose and pancreatic islets that potentially jointly participated in the regulation of plasma insulin. We developed a novel ranking scheme based on cross-loci protein-protein network topology and gene expression to assess each gene's potential to regulate plasma insulin. Unique candidate genes were identified in adipose tissue and islets. In islets, the Alzheimer's gene App was identified as a top candidate regulator. Islets from 17-week-old, but not 10-week-old, App knockout mice showed increased insulin secretion in response to glucose or a membrane-permeant cAMP analog, in agreement with the predictions of the network model. Our result provides a novel hypothesis on the mechanism for the connection between two aging-related diseases: Alzheimer's disease and type 2 diabetes.

Topics: Adipose Tissue; Alzheimer Disease; Amyloid Precursor Protein Secretases; Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Gene Expression Profiling; Gene Regulatory Networks; Glucose; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Leptin; Mice; Mice, Knockout; Mice, Obese; Protein Interaction Maps

Alzheimer's disease (AD) and osteoporosis are common chronic degenerative disorders which are strongly associated with advanced age. Some studies suggest that low bone mineral density (BMD) is related to the increased risk of AD. We conducted a 5-year prospective study to exam the association between BMD and the risk of AD in a cohort of Chinese elderly people. Of 3263 community residents aged 65 years and over, 2019 were enrolled into the study and followed up annually for 5 years. At baseline demographic data, smoking and drinking status, medical history, cognitive status, and blood samples were collected. BMD was measured by dual energy X-ray absorptiometry (DEXA) scanning at baseline and during follow-up. Cox proportional hazards analysis was used to evaluate the association with BMD and incidence of AD. Over the follow-up of 5 years, AD developed in 132 subjects. Baseline BMD, bone loss rate, current smoking, and daily drinking were associated with increased risk of AD, while higher baseline plasma leptin level was associated with decreased risk of AD, in both women and men. Low BMD and increased loss rate of BMD were associated with higher risk of AD. Cigarette smoking, alcohol drinking, and lower leptin level are risk factors for AD. Uncovering the relation linking osteoporosis and AD is important for understanding the pathogenesis and developing therapeutic strategies for these two common disorders afflicting elderly people.

Topics: Aged; Alzheimer Disease; Asian People; Bone Density; Cohort Studies; Female; Follow-Up Studies; Humans; Leptin; Male; Osteoporosis; Prospective Studies; Risk Factors

Alzheimer's disease (AD) is a progressive neurodegenerative disease associated with senile amyloid-β (Aβ) plaques, neuronal death, and cognitive decline. Neurogenesis in the adult hippocampus, which is notably affected by progressive neurodegeneration and Aβ pathology, is implicated in learning and memory regulation. Human postmortem brains of AD patients and AβPP/PS1 double transgenic mice show increased neurodegeneration. Leptin, an adipose-derived hormone, promotes neurogenesis in the adult hippocampus, but the way in which this process occurs in the AD brain is still unknown. Thus, we sought to determine if leptin stimulated the proliferation of neuronal precursors in AβPP/PS1 mice. We estimated the number proliferating hippocampal cells after intracerebroventricular administration of a lentiviral vector encoding leptin. After 3 months of treatment with leptin we observed an increase in the number of BrdU-positive cells in the subgranular zone of the dentate gyrus, as shown by morphometric analysis. This increase resulted mainly from an increased proliferation of neuronal precursors. Additionally, leptin led to an attenuation of Aβ-induced neurodegeneration, as revealed by Fluoro-Jade staining. Our results suggest that in AβPP/PS1 mice, leptin exerts changes resembling acute neurotrophic and neuroprotective effects. These effects could serve as the basis for the design of future treatment strategies in AD.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Cell Proliferation; Cells, Cultured; Cerebral Cortex; Disease Models, Animal; Doublecortin Domain Proteins; Fluoresceins; Gene Expression Regulation; Green Fluorescent Proteins; Humans; Indoles; Leptin; Male; Mice; Mice, Transgenic; Microtubule-Associated Proteins; Neural Stem Cells; Neuropeptides; Neuroprotective Agents; Organic Chemicals; Presenilin-1; Rats; Rats, Wistar

Both tumor necrosis factor (TNF) and leptin are, independently, under investigation as the central mechanism for Alzheimer's disease. The wider literature provides every indication that both mediators are part of the same pathways thought to cause functional loss in this condition. This association, which has not been specifically addressed in the Alzheimer's disease literature, may be a useful link to expedite future study into the pathogenesis of this condition.

Topics: Alzheimer Disease; Humans; Leptin; Tumor Necrosis Factor-alpha

Alzheimer's disease (AD) and atherosclerosis share common vascular risk factors such as arterial hypertension and hypercholesterolemia. Adipocytokines and CD34(+) progenitor cells are associated with the progression and prognosis of atherosclerotic diseases. Their role in AD is not adequately elucidated.. In the present study, we measured in 41 patients with early AD and 37 age- and weight-matched healthy controls blood concentrations of adiponectin and leptin by enzyme linked immunoabsorbent assay and of CD34(+) progenitor cells using flow cytometry. We found significantly lower plasma levels of leptin in AD patients compared with the controls, whereas plasma levels of adiponectin did not show any significant differences (AD vs. control (mean ± SD): leptin:8.9 ± 5.6 ng/mL vs.16.3 ± 15.5 ng/mL;P = 0.038; adiponectin:18.5 ± 18.1 µg/mL vs.16.7 ± 8.9 µg/mL;P = 0.641). In contrast, circulating CD34(+) cells were significantly upregulated in AD patients (mean absolute cell count ± SD:253 ± 51 vs. 203 ± 37; P = 0.02) and showed an inverse correlation with plasma levels of leptin (r =  -0.248; P = 0.037). In logistic regression analysis, decreased leptin concentration (P = 0.021) and increased number of CD34(+) cells (P = 0.036) were both significantly associated with the presence of AD. According to multifactorial analysis of covariance, leptin serum levels were a significant independent predictor for the number of CD34(+) cells (P = 0.002).. Our findings suggest that low plasma levels of leptin and increased numbers of CD34(+) progenitor cells are both associated with AD. In addition, the results of our study provide first evidence that increased leptin plasma levels are associated with a reduced number of CD34(+) progenitor cells in AD patients. These findings point towards a combined involvement of leptin and CD34(+) progenitor cells in the pathogenesis of AD. Thus, plasma levels of leptin and circulating CD34(+) progenitor cells could represent an important molecular link between atherosclerotic diseases and AD. Further studies should clarify the pathophysiological role of both adipocytokines and progenitor cells in AD and possible diagnostic and therapeutic applications.

Topics: Adiponectin; Aged; Aged, 80 and over; Alzheimer Disease; Antigens, CD34; Cell Count; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Hematopoietic Stem Cells; Humans; Leptin; Logistic Models; Male; Middle Aged

Leptin is a pleiotropic hormone primarily secreted by adipocytes. A high density of functional Leptin receptors has been reported to be expressed in the hippocampus and other cortical regions of the brain, the physiological significance of which has not been explored extensively. Alzheimer's disease (AD) is marked by impaired brain metabolism with decreased glucose utilization in those regions which often precede pathological changes. Recent epidemiological studies suggest that plasma Leptin is protective against AD. Specifically, elderly with plasma Leptin levels in the lowest quartile were found to be four times more likely to develop AD than those in the highest quartile. We have previously reported that Leptin modulates AD pathological pathways in vitro through a mechanism involving the energy sensor, AMP-activated protein kinase (AMPK). To this end, we investigated the extent to which activation of AMPK as well as another class of sensors linking energy availability to cellular metabolism, the sirtuins (SIRT), mediate Leptin's biological activity. Leptin directly activated neuronal AMPK and SIRT in cell lines. Additionally, the ability of Leptin to reduce tau phosphorylation and β-amyloid production was sensitive to the AMPK and sirtuin inhibitors, compound C and nicotinamide, respectively. These findings implicate that Leptin normally acts as a signal for energy homeostasis in neurons. Perhaps Leptin deficiency in AD contributes to a neuronal imbalance in handling energy requirements, leading to higher Aβ and phospho-tau, which can be restored by replenishing low Leptin levels. This may also be a legitimate strategy for therapy.

Topics: Alzheimer Disease; AMP-Activated Protein Kinase Kinases; Amyloid; Amyloid beta-Peptides; Cell Line, Tumor; Enzyme Activation; Humans; Leptin; Neurons; Phosphorylation; Protein Kinases; Sirtuins; tau Proteins

Accumulation of amyloid-beta (Abeta) peptide and deposition of hyperphosphorylated tau protein are two major pathological hallmarks of Alzheimer's disease (AD). We have shown that cholesterol-enriched diets and its metabolite 27-hydroxycholesterol (27-OHC) increase Abeta and phosphorylated tau levels. However, the mechanisms by which cholesterol and 27-OHC regulate Abeta production and tau phosphorylation remain unclear. Leptin, an adipocytokine involved in cell survival and in learning, has been demonstrated to regulate Abeta production and tau hyperphosphorylation in transgenic mice for AD. However, the involvement of leptin signaling in cholesterol and cholesterol metabolites-induced Abeta accumulation and tau hyperphosphorylation are yet to be examined. In this study, we determined the effect of high cholesterol diet and 27-OHC on leptin expression levels and the extent to which leptin treatment affects 27-OHC-induced AD-like pathology. Our results show that feeding rabbits a 2% cholesterol-enriched diet for 12 weeks reduces the levels of leptin by approximately 80% and incubating organotypic slices from adult rabbit hippocampus with 27-OHC reduced leptin levels by approximately 30%. 27-OHC induces a 1.5-fold increase in Abeta (40) and a 3-fold increase in Abeta (42) and in phosphorylated tau. Treatment with leptin reversed the 27-OHC-induced increase in Abeta and phosphorylated tau by decreasing the levels of BACE-1 and GSK-3beta respectively. Our results suggest that cholesterol-enriched diets and cholesterol metabolites induce AD-like pathology by altering leptin signaling. We propose that leptin administration may prevent the progression of sporadic forms of AD that are related to increased cholesterol and oxidized cholesterol metabolite levels.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Blotting, Western; Enzyme-Linked Immunosorbent Assay; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hippocampus; Hydroxycholesterols; Leptin; Male; Organ Culture Techniques; Phosphorylation; Rabbits; tau Proteins

Recent studies suggest that hyperinsulinemia and insulin resistance are linked to Alzheimer's disease (AD). In this study, we used Tg2576 transgenic (Tg) mice, a widely used transgenic mouse model for AD, to explore the relationship between increased amyloid beta-peptide (Abeta) and insulin resistance. When fed a high-fat diet (HFD), Tg mice developed obesity and insulin resistance at 16 wk of age. Furthermore, HFD-fed Tg mice displayed abnormal feeding behavior and increased caloric intake with time. Although caloric intake of HFD-fed Tg mice was similar to that of normal diet-fed Tg or wild-type mice during 4 to 8 wk of age, it increased sharply at 12 wk, and went up further at 16 wk, which paralleled changes in the level of Abeta40 and Abeta42 in the brain of these mice. Limiting food intake in HFD-fed Tg mice by pair-feeding a caloric intake identical with that of normal diet-fed mice completely prevented the obesity and insulin intolerance of HFD-fed Tg mice. The hypothalamus of HFD-fed Tg mice had a significant decrease in the expression of the anorexigenic neuropeptide, brain-derived neurotrophic factor, at both the mRNA and protein levels. These findings suggest that the increased Abeta in the brain of HFD-fed Tg2576 mice is associated with reduced brain-derived neurotrophic factor expression, which led to abnormal feeding behavior and increased food intake, resulting in obesity and insulin resistance in these animals.

Topics: Adipose Tissue; Alzheimer Disease; Amyloid beta-Peptides; Analysis of Variance; Animals; Blotting, Western; Brain-Derived Neurotrophic Factor; Dietary Fats; Disease Models, Animal; Eating; Energy Intake; Fluorescent Antibody Technique; Ghrelin; Glucose Tolerance Test; Hypothalamus; Insulin Resistance; Leptin; Mice; Motor Activity; Obesity; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Satiety Response; Time Factors

Topics: Alzheimer Disease; Animals; Humans; Incidence; Leptin; Risk Factors

We have previously reported anti-amyloidogenic effects of leptin using in vitro and in vivo models and, more recently, demonstrated the ability of leptin to reduce tau phosphorylation in neuronal cells. The present study examined the efficacy of leptin in ameliorating the Alzheimer's disease (AD)-like pathology in 6-month old CRND8 transgenic mice (TgCRND8) following 8 weeks of treatment. Leptin-treated transgenic mice showed significantly reduced levels of amyloid-beta (Abeta){1-40} in both brain extracts (52% reduction, p= 0.047) and serum (55% reduction, p= 0.049), as detected by ELISA, and significant reduction in amyloid burden (47% reduction, p=0.041) in the hippocampus, as detected by immunocytochemistry. The decrease in the levels of Abeta in the brain correlated with a decrease in the levels of C99 C-terminal fragments of the amyloid-beta protein precursor, consistent with a role for beta -secretase in mediating the effect of leptin. In addition, leptin-treated TgCRND8 mice had significantly lower levels of phosphorylated tau, as detected by AT8 and anti-tau-Ser{396} antibodies. Importantly, after 4 or 8 weeks of treatment, there was no significant increase in the levels of C-reactive protein, tumor necrosis factor-alpha, and cortisol in the plasma of leptin-treated TgCRND8 animals compared to saline-treated controls, indicating no inflammatory reaction. These biochemical and pathological changes were correlated with behavioral improvements, as early as after 4 weeks of treatment, as recorded by a novel object recognition test and particularly the contextual and cued fear conditioning test after 8 weeks of treatment. Leptin-treated TgCRND8 animals significantly outperformed saline-treated littermates in these behavioral tests. These findings solidly demonstrate the potential for leptin as a disease modifying therapeutic in transgenic animals of AD, driving optimism for its safety and efficacy in humans.

Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Animals; C-Reactive Protein; Conditioning, Psychological; Disease Models, Animal; Fear; Hippocampus; Immunohistochemistry; Infusion Pumps, Implantable; Leptin; Memory Disorders; Mice; Mice, Transgenic; Neurons; Phosphorylation; Recognition, Psychology; tau Proteins

Topics: Adipose Tissue; Alzheimer Disease; Brain; Humans; Leptin; Obesity; Reproducibility of Results

Leptin, which serves as a lipid-modulating hormone to control metabolic energy availability, is decreased in Alzheimer's disease (AD) patients, and serum levels are inversely correlated to severity of dementia. We have previously described the effects of leptin in reducing amyloid beta protein both in vitro and in vivo, and tau phosphorylation in vitro. Herein, we systematically investigated the signaling pathways activated by leptin, leading to these molecular endpoints, to better understand its mechanism of action. Inhibition of amyloid beta production and tau phosphorylation in leptin-treated human and/or rat neuronal cultures were both dependent on activation of AMP-activated protein kinase (AMPK). Direct stimulation of AMPK with the cell-permeable activator, 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR), replicated leptin's effects and conversely, Compound C, an inhibitor of AMPK, blocked leptin's action. The data implicate that AMPK is a key regulator of both AD-related pathways.

Topics: Alzheimer Disease; Aminoimidazole Carboxamide; AMP-Activated Protein Kinase Kinases; Amyloid beta-Peptides; Animals; Cells, Cultured; Humans; Leptin; Neurons; Phosphorylation; Protein Kinase Inhibitors; Protein Kinases; Pyrazoles; Pyrimidines; Rats; Ribonucleotides; tau Proteins

Topics: Aged; Alzheimer Disease; C-Reactive Protein; Dementia; Humans; Leptin; Middle Aged; Obesity; Risk

We have previously demonstrated that Leptin reduces extracellular amyloid beta (Abeta) protein both in vitro and in vivo, and intracellular tau phosphorylation in vitro. Further, we have shown that these effects are dependent on activation of AMP-activated protein kinase (AMPK) in vitro. Herein, we investigated downstream effectors of AMPK signaling directly linked to tau phosphorylation. One such target, of relevance to Alzheimer's disease (AD), may be GSK-3beta, which has been shown to be inactivated by Leptin. We therefore dissected the role of GSK-3beta in mediating Leptin's ability to reduce tau phosphorylation in neuronal cells. Our data suggest that Leptin regulates tau phosphorylation through a pathway involving both AMPK and GSK-3beta. This was based on the following: Leptin and the cell-permeable AMPK activator, 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR), reduced tau phosphorylation at AD-relevant sites similarly to the GSK-3beta inhibitor, lithium chloride (LiCl). Further, this reduction of tau phosphorylation was mimicked by the downregulation of GSK-3beta, achieved using siRNA technology and antagonized by the ectopic overexpression of GSK-3beta. These studies provide further insight into Leptin's mechanism of action in suppressing AD-related pathways.

Topics: Alzheimer Disease; Aminoimidazole Carboxamide; AMP-Activated Protein Kinases; Antimanic Agents; Brain; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Hypoglycemic Agents; Leptin; Lithium Chloride; Neurofibrillary Tangles; Neurons; Phosphorylation; Ribonucleotides; Signal Transduction; tau Proteins; Tumor Cells, Cultured

Topics: Alzheimer Disease; Animals; Butyrylcholinesterase; Carrier Proteins; Cholinesterase Inhibitors; Clinical Trials as Topic; Drug Evaluation, Preclinical; Drugs, Investigational; Histamine H3 Antagonists; Humans; Leptin; Membrane Proteins; Nerve Tissue Proteins; tau Proteins; Tumor Necrosis Factor-alpha

The adipokine leptin facilitates long-term potentiation and synaptic plasticity in the hippocampus, promotes beta-amyloid clearance, and improves memory function in animal models of aging and Alzheimer disease (AD).. To relate baseline circulating leptin concentrations in a community-based sample of individuals without dementia to incident dementia and AD during follow-up and magnetic resonance imaging (MRI) measures of brain aging in survivors.. Prospective study of plasma leptin concentrations measured in 785 persons without dementia (mean [SD] age, 79 [5] years; 62% female), who were in the Framingham original cohort at the 22nd examination cycle (1990-1994). A subsample of 198 dementia-free survivors underwent volumetric brain MRI between 1999 and 2005, approximately 7.7 years after leptin was assayed. Two measures of brain aging, total cerebral brain volume and temporal horn volume (which is inversely related to hippocampal volume) were assessed.. Incidence of dementia and AD during follow-up until December 31, 2007.. During a median follow-up of 8.3 years (range, 0-15.5 years), 111 participants developed incident dementia; 89 had AD. Higher leptin levels were associated with a lower risk of incident dementia and AD in multivariable models (hazard ratio per 1-SD increment in log leptin was 0.68 [95% confidence interval, 0.54-0.87] for all-cause dementia and 0.60 [95% confidence interval, 0.46-0.79] for AD). This corresponds to an absolute AD risk over a 12-year follow-up of 25% for persons in the lowest quartile (first quartile) vs 6% for persons in the fourth quartile of sex-specific leptin levels. In addition, a 1-SD elevation in plasma leptin level was associated with higher total cerebral brain volume and lower temporal horn volume, although the association of leptin level with temporal horn volume did not reach statistical significance.. Circulating leptin was associated with a reduced incidence of dementia and AD and with cerebral brain volume in asymptomatic older adults.

Topics: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Brain; Dementia; Female; Follow-Up Studies; Humans; Leptin; Magnetic Resonance Imaging; Male; Prospective Studies

Topics: Aging; Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Comorbidity; Cost of Illness; Dementia; Enzyme Inhibitors; Flurbiprofen; Global Health; Humans; Leptin; Longevity; Peptide Fragments

Leptin is a centrally acting hormone controlling metabolic pathways. Recently, it was shown that leptin can reduce amyloid beta levels both in vitro and in vivo. Herein, phosphorylation of tau was investigated following treatment of neuronal cells with leptin and insulin. Specifically, phosphorylation of tau at amino acid residues Ser(202), Ser(396) and Ser(404) was monitored in retinoic acid induced, human cell lines: SH-SY5Y and NTera-2. Both hormones induced a concentration- and time-dependent reduction of tau phosphorylation, and were synergistic at suboptimum concentrations. Importantly, leptin was 300-fold more potent than insulin (IC(50)L=46.9 nM vs. IC(50)I=13.8 microM). A central role for AMP-dependent kinase as a mediator of leptin's action is demonstrated by the ability of 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR) to decrease tau phosphorylation, and by blocking leptin in the presence of Compound C. Thus, leptin, which ameliorates both amyloid beta and tau-related pathological pathways, holds promise as a novel therapeutic for Alzheimer's disease.

Topics: Alzheimer Disease; Aminoimidazole Carboxamide; AMP-Activated Protein Kinases; Cell Line, Tumor; Humans; Insulin; Leptin; Multienzyme Complexes; Neurons; Phosphorylation; Protein Serine-Threonine Kinases; Pyrazoles; Pyrimidines; Ribonucleotides; Signal Transduction; tau Proteins

Leptin, a peptide hormone secreted by adipose tissue, exhibits a large range of central and peripheral actions. It has been proposed that the participation of leptin in diseases such as obesity is due to, at least in part, its impaired transport across the blood-brain barrier (BBB). Since, the mechanisms by which brain takes up leptin remain unclear, we set out to study how leptin may cross the BBB. We have used different immunoassays and lentiviral vectors to analyze the role of megalin in the transport of leptin in rodents and humans. We demonstrate that circulating leptin is transported into the brain by binding to megalin at the choroid plexus epithelium. Indeed, the downregulation of megalin expression in physiological and pathological situations such as aging and Alzheimer's disease was correlated with poor entry of leptin into the brain. Moreover, amyloid beta (Abeta) deposits of choroid plexus could be disturbing megalin function. The present data indicate that leptin represents a novel megalin ligand of importance in the levels and therapeutic actions of leptin into the brain.

Topics: Aged; Aging; Alzheimer Disease; Animals; Biological Transport, Active; Blood-Brain Barrier; Cerebrospinal Fluid; Choroid Plexus; Female; Humans; Leptin; Low Density Lipoprotein Receptor-Related Protein-2; Male; Rats; Rats, Wistar; Signal Transduction

Frontotemporal lobar degeneration (FTLD) includes different heterogeneous conditions, mainly characterised by personality changes, along with cognitive deficits in language and executive functions. Movement disorders are variably represented. Behavioural disturbances constitute the core feature of FTLD, and eating disorders represent one of the most distinguishing symptoms between FTLD and Alzheimer's disease (AD). The biochemical correlates of such dysfunctions remain to be defined. The adipocyte derived hormone leptin is known to play a foundamental role in food intake and energy balance. To understand whether leptin could be involved in FTLD eating abnormalities, we measured serum leptin levels in 59 patients with FTLD compared with 25 with AD. Serum leptin levels in patients with FTLD were comparable with those in patients with AD. Nevertheless, females with FTLD showed significantly higher leptin levels compared with females with AD. No difference was found between FTDL and AD males or within the spectrum of patients with FTLD. Hyperphagic FTLD females showed higher circulating leptin levels in comparison with those without eating abnormalities; no differences were found between males with FTLD with respect to serum leptin and food intake disturbances. The present study showed a selective gender difference in leptin levels between females with FTLD and AD, which may suggest specific cognitive and behavioural networks need to be investigated.

Topics: Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; Dementia; Female; Humans; Hyperphagia; Leptin; Male; Mental Status Schedule; Middle Aged; Neuropsychological Tests; Reference Values; Sex Factors

Abeta peptide is the major proteinateous component of the amyloid plaques found in the brains of Alzheimer's disease (AD) patients and is regarded by many as the culprit of the disorder. It is well documented that brain lipids are intricately involved in Abeta-related pathogenic pathways. An important modulator of lipid homeostasis is the pluripotent peptide leptin. Here we demonstrate leptin's ability to modify Abeta levels in vitro and in vivo. Similar to methyl-beta-cyclodextrin, leptin reduces beta-secretase activity in neuronal cells possibly by altering the lipid composition of membrane lipid rafts. This phenotype contrasts treatments with cholesterol and etomoxir, an inhibitor of carnitine-palmitoyl transferase-1. Conversely, inhibitors of acetyl CoA carboxylase and fatty acid synthase mimicked leptin's action. Leptin was also able to increase apoE-dependent Abeta uptake in vitro. Thus, leptin can modulate bidirectional Abeta kinesis, reducing its levels extracellularly. Most strikingly, chronic administration of leptin to AD-transgenic animals reduced the brain Abeta load, underlying its therapeutic potential.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; CCAAT-Enhancer-Binding Proteins; Cells, Cultured; DNA-Binding Proteins; Humans; Leptin; Membrane Microdomains; Mice; Mice, Transgenic; Neurons; Obesity; Peptide Fragments; Rats; Sterol Regulatory Element Binding Protein 1; Sterol Regulatory Element Binding Protein 2; Transcription Factors

High-fat diet alters apo E-dependent processing of beta-amyloid precursor protein. Here we have evaluated the effects of dietary fat on brain apo E mRNA in Zucker lean and obese rats. After approximately 2 months on a high-fat diet, there was significant up-regulation of brain apo E mRNA in the Zucker lean rat in parallel with weight gain. Densitometric quantification revealed a 17% increase in apo E mRNA in the brains of lean rats fed high-fat diet compared with those of lean rats fed rat chow. No significant difference in brain apo E mRNA of Zucker obese rats fed different diets was found. These results suggest that dietary fat alters brain apo E levels, which may be regulated, in part, through the leptin receptor.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Apolipoproteins E; Appetite Regulation; Brain; Brain Chemistry; Carrier Proteins; Dietary Fats; Eating; Food, Formulated; Leptin; Obesity; Rats; Rats, Zucker; Receptors, Cell Surface; Receptors, Leptin; RNA, Messenger; Up-Regulation; Weight Gain

Topics: Aged; Alzheimer Disease; Circadian Rhythm; Female; Humans; Hydrocortisone; Leptin; Male; Proteins