exenatide and Alzheimer-Disease

Type 2 diabetes has been identified as a risk factor for Alzheimer's disease (AD) and Parkinson's disease (PD). In the brains of patients with AD and PD, insulin signaling is impaired. This finding has motivated new research that showed good effects using drugs that initially had been developed to treat diabetes. Preclinical studies showed good neuroprotective effects applying insulin or long lasting analogues of incretin peptides. In transgenic animal models of AD or PD, analogues of the incretin GLP-1 prevented neurodegenerative processes and improved neuronal and synaptic functionality and reduced the symptoms of the diseases. Amyloid plaque load and synaptic loss as well as cognitive impairment had been prevented in transgenic AD mouse models, and dopaminergic loss of transmission and motor function has been reversed in animal models of PD. On the basis of these promising findings, several clinical trials are being conducted with the first encouraging clinical results already published. In several pilot studies in AD patients, the nasal application of insulin showed encouraging effects on cognition and biomarkers. A pilot study in PD patients testing a GLP-1 receptor agonist that is currently on the market as a treatment for type 2 diabetes (exendin-4, Byetta) also showed encouraging effects. Several other clinical trials are currently ongoing in AD patients, testing another GLP-1 analogue that is on the market (liraglutide, Victoza). Recently, a third GLP-1 receptor agonist has been brought to the market in Europe (Lixisenatide, Lyxumia), which also shows very promising neuroprotective effects. This review will summarise the range of these protective effects that those drugs have demonstrated. GLP-1 analogues show promise in providing novel treatments that may be protective or even regenerative in AD and PD, something that no current drug does.

Topics: Alzheimer Disease; Animals; Diabetes Mellitus, Type 2; Disease Models, Animal; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Liraglutide; Mice; Mice, Transgenic; Neuroprotective Agents; Parkinson Disease; Peptides; Receptors, Glucagon; Venoms

The glucagon-like peptide-1 (GLP-1) mimetics are an established therapeutic option for patients with type 2 diabetes. However, the properties of the GLP-1 mimetics go beyond the strict metabolic control of the patients with diabetes. The neuroprotective effects of GLP-1 have been shown in recent studies opening new areas of research in neurodegenerative diseases such as Alzheimer's disease (AD), among others. AIM. Systematic review including experimental studies and human clinical trials demonstrating the neuroprotective properties of GLP-1 mimetics in AD.. The experimental studies that have been conducted in rodent models of AD have demonstrated the neuroprotective properties of GLP-1 in the central nervous system reducing beta-amyloid plaques, the oxidative stress and the inflammatory brain response. Clinical trials in patients with cognitive impairment and AD testing the effects of GLP-1 analogs have recently started.. The GLP-1 analogs have neuroprotective properties. Considering that type 2 diabetes is a risk factor for cognitive impairment and dementia, the benefits of GLP-1 mimetics on cognition must be considered. Likewise, the GLP-1 mimetics represent a promising treatment for neurodegenerative diseases such as AD.. Analogos del glucagon-like peptide-1 (GLP-1): una nueva estrategia de tratamiento para la enfermedad de Alzheimer?. Introduccion. Los analogos del glucagon-like peptide-1 (GLP-1) son una opcion terapeutica establecida en los pacientes con diabetes tipo 2. Sin embargo, las propiedades de los analogos del GLP-1 van mas alla del control estrictamente metabolico del paciente diabetico. Los efectos neuroprotectores de los analogos del GLP-1 se han puesto de manifiesto en estudios recientes y han abierto nuevos campos de investigacion en trastornos neurodegenerativos como la enfermedad de Alzheimer (EA), entre otros. Objetivo. Revision sistematica de los estudios experimentales y ensayos clinicos en humanos que demuestran las propiedades neuroprotectoras de los analogos del GLP-1 en la EA. Desarrollo. Los estudios experimentales que se han llevado a cabo en modelos de roedores con EA demuestran las propiedades neuroprotectoras de los analogos del GLP-1 sobre el sistema nervioso central que reducen las placas de beta-amiloide, el estres oxidativo y la respuesta inflamatoria cerebral. Recientemente se han puesto en marcha estudios con analogos del GLP-1 en humanos con deterioro cognitivo y EA. Conclusiones. Los analogos del GLP-1 presentan propiedades neuroprotectoras. Al considerarse la diabetes tipo 2 un factor de riesgo para el deterioro cognitivo y la demencia, deben considerarse los beneficios de los analogos del GLP-1 sobre la cognicion. Del mismo modo, los analogos del GLP-1 suponen un tratamiento prometedor en la EA.

Topics: Alzheimer Disease; Animals; Blood-Brain Barrier; Brain Chemistry; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Drug Evaluation, Preclinical; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Insulin Resistance; Liraglutide; Models, Neurological; Neuroprotective Agents; Peptides; Randomized Controlled Trials as Topic; Receptors, Glucagon; Risk Factors; Venoms

According to World Health Organization estimates, type 2 diabetes (T2D) is an epidemic (particularly in under development countries) and a socio-economic challenge. This is even more relevant since increasing evidence points T2D as a risk factor for Alzheimer's disease (AD), supporting the hypothesis that AD is a "type 3 diabetes" or "brain insulin resistant state". Despite the limited knowledge on the molecular mechanisms and the etiological complexity of both pathologies, evidence suggests that neurodegeneration/death underlying cognitive dysfunction (and ultimately dementia) upon long-term T2D may arise from a complex interplay between T2D and brain aging. Additionally, decreased brain insulin levels/signaling and glucose metabolism in both pathologies further suggests that an effective treatment strategy for one disorder may be also beneficial in the other. In this regard, one such promising strategy is a novel successful anti-T2D class of drugs, the glucagon-like peptide-1 (GLP-1) mimetics (e.g. exendin-4 or liraglutide), whose potential neuroprotective effects have been increasingly shown in the last years. In fact, several studies showed that, besides improving peripheral (and probably brain) insulin signaling, GLP-1 analogs minimize cell loss and possibly rescue cognitive decline in models of AD, Parkinson's (PD) or Huntington's disease. Interestingly, exendin-4 is undergoing clinical trials to test its potential as an anti-PD therapy. Herewith, we aim to integrate the available data on the metabolic and neuroprotective effects of GLP-1 mimetics in the central nervous system (CNS) with the complex crosstalk between T2D-AD, as well as their potential therapeutic value against T2D-associated cognitive dysfunction.

Topics: Alzheimer Disease; Biomimetics; Brain; Central Nervous System; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glucose; Humans; Insulin Resistance; Liraglutide; Peptides; Venoms

Glucagon-like peptide 1 (GLP-1) is a relatively recently discovered molecule originating in the so-called L-cells of the intestine. The peptide has insulinotrophic properties and it is this characteristic that has predominantly been investigated. This has led to the use of the GLP-1-like peptide exendin-4 (EX-4), which has a much longer plasma half-life than GLP-1 itself, being used in the treatment of type II diabetes. The mode of action of this effect appears to be a reduction in pancreatic apoptosis, an increase in beta cell proliferation or both. Thus, the effects of GLP-1 receptor stimulation are not based upon insulin replacement but an apparent repair of the pancreas. Similar data suggest that the same effects may occur in other peripheral tissues. More recently, the roles of GLP-1 and EX-4 have been studied in nervous tissue. As in the periphery, both peptides appear to promote cellular growth and reduce apoptosis. In models of Alzheimer's disease, Parkinson's disease and peripheral neuropathy, stimulation of the GLP-1 receptor has proved to be highly beneficial. In the case of Parkinson's disease this effect is evident after the neurotoxic lesion is established, suggesting real potential for therapeutic use. In the present review we examine the current status of the GLP-1 receptor and its potential as a therapeutic target.

Topics: Alzheimer Disease; Animals; Apoptosis; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Half-Life; Insulin; Insulin-Secreting Cells; Intestines; Neuroprotective Agents; Pancreas; Peptides; Receptors, Glucagon; Venoms

Strong preclinical evidence suggests that exenatide, a glucagon-like peptide-1 (GLP- 1) receptor agonist used for treating type 2 diabetes, is neuroprotective and disease-modifying in Alzheimer's Disease (AD).. We performed an 18-month double-blind randomized placebo-controlled Phase II clinical trial to assess the safety and tolerability of exenatide and explore treatment responses for clinical, cognitive, and biomarker outcomes in early AD.. Eighteen participants with high probability AD based on cerebrospinal fluid (CSF) biomarkers completed the entire study prior to its early termination by the sponsor; partial outcomes were available for twentyone.. Exenatide was safe and well-tolerated, showing an expectedly higher incidence of nausea and decreased appetite compared to placebo and decreasing glucose and GLP-1 during Oral Glucose Tolerance Tests. Exenatide treatment produced no differences or trends compared to placebo for clinical and cognitive measures, MRI cortical thickness and volume, or biomarkers in CSF, plasma, and plasma neuronal extracellular vesicles (EV) except for a reduction of Aβ42 in EVs.. The positive finding of lower EV Aβ42 supports emerging evidence that plasma neuronal EVs provide an effective platform for demonstrating biomarker responses in clinical trials in AD. The study was underpowered due to early termination and therefore we cannot draw any firm conclusions. However, the analysis of secondary outcomes shows no trends in support of the hypothesis that exenatide is diseasemodifying in clinical AD, and lowering EV Aβ42 in and of itself may not improve cognitive outcomes in AD.

Topics: Aged; Alzheimer Disease; Biomarkers; Brain; Cognitive Dysfunction; Double-Blind Method; Exenatide; Female; Glucagon-Like Peptide 1; Humans; Male; Neuroprotective Agents; Neuropsychological Tests; Pilot Projects

Type 2 diabetes (T2D) is an independent risk factor for Alzheimer's disease (AD). Exendin-4 (Ex-4), a widely used glucagon-like peptide-1 receptor agonist drug in the treatment of T2D, has been demonstrated the therapeutic effects on diabetic encephalopathy (DE). Especially, the Ex-4 ameliorates the tau hyperphosphorylation and cognitive impairment in DE. And these crucial alterations are also important bridge between T2D and AD. However, its unique mechanism is unclear.. The db/db mice, high-fat-diet (HFD) / streptozotocin (STZ)-induced diabetic (HF-diabetic) mice, and high-glucose-damaged (HGD) HT-22 hippocampal cells were enrolled to examine the effects of Ex-4 on AD-like changes in T2D. The Novel object recognition test (NORT) and Morris water maze test (MWMT) were conducted to evaluate the cognitive impairment. The Dickkopf-1 (DKK1) was employed to weaken the activation of the Wnt/β-catenin pathway to explore the mechanism of Ex-4 in protecting the brain functions. The JASPAR was based to predict the interaction between NeuroD1 and the promoter region of Ins2. Moreover, the chromatin immunoprecipitation coupled with quantitative polymerase chain reaction (ChIP-qPCR) and luciferase reporter assays were performed.. Ex-4 alleviated the tau hyperphosphorylation, increased the brain-derived insulin, and improved the PI3K/AKT/GSK3-β signalling in db/db mice, HF-diabetic mice, and HGD HT-22 hippocampal neuronal cells. The NORT and MWMT indicated that Ex-4 alleviated the learning and memory deficits in HF-diabetic mice. The inhibitor Dickkopf-1 (DKK1) of the Wnt/β-catenin pathway significantly blocked the protective effects of Ex-4. Regarding further molecular mechanisms, NeuroD1 was affected by Ex-4 in vivo and in vitro, and the knockdown or overexpression of NeuroD1 suggested its crucial role in promoting the brain insulin by Ex-4. Meanwhile, the ChIP‒qPCR and luciferase reporter assays confirmed the combination between NeuroD1 and the promoter region of the insulin-encoding gene Ins2. And this interaction could be promoted by Ex-4.. Our study proposes that Ex-4 alleviates tau hyperphosphorylation and cognitive dysfunction by increasing Ins2-derived brain insulin through the Wnt/β-catenin/NeuroD1 signaling in T2D. And its also show new lights on part of the progress and mechanism on treatment targets for the DE in T2D.

Topics: Alzheimer Disease; Animals; beta Catenin; Cognitive Dysfunction; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Exenatide; Glycogen Synthase Kinase 3; Insulin; Mice; Phosphatidylinositol 3-Kinases

Alzheimer's disease (AD) is the most common cause of age-related dementia. Increasing evidence suggests that neuroinflammation mediated by microglia and astrocytes contributes to disease progression and severity in AD and other neurodegenerative disorders. During AD progression, resident microglia undergo proinflammatory activation, resulting in an increased capacity to convert resting astrocytes to reactive astrocytes. Therefore, microglia are a major therapeutic target for AD and blocking microglia-astrocyte activation could limit neurodegeneration in AD. Here we report that NLY01, an engineered exedin-4, glucagon-like peptide-1 receptor (GLP-1R) agonist, selectively blocks β-amyloid (Aβ)-induced activation of microglia through GLP-1R activation and inhibits the formation of reactive astrocytes as well as preserves neurons in AD models. In two transgenic AD mouse models (5xFAD and 3xTg-AD), repeated subcutaneous administration of NLY01 blocked microglia-mediated reactive astrocyte conversion and preserved neuronal viability, resulting in improved spatial learning and memory. Our study indicates that the GLP-1 pathway plays a critical role in microglia-reactive astrocyte associated neuroinflammation in AD and the effects of NLY01 are primarily mediated through a direct action on Aβ-induced GLP-1R

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Astrocytes; Cells, Cultured; Exenatide; Glucagon-Like Peptide-1 Receptor; Humans; Male; Maze Learning; Mice; Mice, Transgenic; Microglia; Neuroprotection; Neuroprotective Agents; Peptide Fragments

Pharmacological reversal of brain aging is a long-sought yet challenging strategy for the prevention and treatment of age-related neurodegeneration, due to the diverse cell types and complex cellular pathways impacted by the aging process. Here, we report the genome-wide reversal of transcriptomic aging signatures in multiple major brain cell types, including glial and mural cells, by systemic glucagon-like peptide-1 receptor (GLP-1R) agonist (GLP-1RA) treatment. The age-related expression changes reversed by GLP-1RA encompass both shared and cell type-specific functional pathways that are implicated in aging and neurodegeneration. Concomitantly, Alzheimer's disease (AD)-associated transcriptomic signature in microglia that arises from aging is reduced. These results show the feasibility of reversing brain aging by pharmacological means, provide mechanistic insights into the neurological benefits of GLP-1RAs, and imply that GLP-1R agonism may be a generally applicable pharmacological intervention for patients at risk of age-related neurodegeneration.

Topics: Aging; Alzheimer Disease; Animals; Brain; Cellular Senescence; Exenatide; Feasibility Studies; Glucagon-Like Peptide-1 Receptor; Humans; Male; Mice; Mice, Inbred C57BL; Neurodegenerative Diseases; Neuroglia; Transcriptome

Topics: Alzheimer Disease; Amino Acid Sequence; Animals; Blood-Brain Barrier; Brain; Exenatide; Humans; Incretins; Male; Mice; Parkinson Disease

The molecular signatures of cells in the brain have been revealed in unprecedented detail, yet the ageing-associated genome-wide expression changes that may contribute to neurovascular dysfunction in neurodegenerative diseases remain elusive. Here, we report zonation-dependent transcriptomic changes in aged mouse brain endothelial cells (ECs), which prominently implicate altered immune/cytokine signaling in ECs of all vascular segments, and functional changes impacting the blood-brain barrier (BBB) and glucose/energy metabolism especially in capillary ECs (capECs). An overrepresentation of Alzheimer disease (AD) GWAS genes is evident among the human orthologs of the differentially expressed genes of aged capECs, while comparative analysis revealed a subset of concordantly downregulated, functionally important genes in human AD brains. Treatment with exenatide, a glucagon-like peptide-1 receptor agonist, strongly reverses aged mouse brain EC transcriptomic changes and BBB leakage, with associated attenuation of microglial priming. We thus revealed transcriptomic alterations underlying brain EC ageing that are complex yet pharmacologically reversible.

Topics: Aging; Alzheimer Disease; Animals; Blood-Brain Barrier; Brain; Capillaries; Cells, Cultured; Endothelial Cells; Exenatide; Humans; Mice; Microglia; Neurodegenerative Diseases; Transcriptome

Disruption of brain insulin signaling may explain the higher Alzheimer's disease (AD) risk among type 2 diabetic (T2D) patients. There is evidence from in vitro and human postmortem studies that combination of insulin with hypoglycemic medications is neuroprotective and associated with less amyloid aggregation. We examined the effect of 8-month intranasal administration of insulin, exenatide (a GLP-1 agonist), combination therapy (insulin + exenatide) or saline, in wild-type (WT) and an AD-like mouse model (Tg2576). Mice were assessed for learning, gene expression of key mediators and effectors of the insulin receptor signaling pathway (IRSP-IRS1, AKT1, CTNNB1, INSR, IRS2, GSK3B, IGF1R, AKT3), and brain Amyloid Beta (Aβ) levels. In Tg2576 mice, combination therapy reduced expression of IRSP genes which was accompanied by better learning. Cortical Aβ levels were decreased by 15-30% in all groups compared to saline but this difference did not reach statistical significance. WT mice groups, with or without treatment, did not differ in any comparison. Disentangling the mechanisms underlying the potential beneficial effects of combination therapy on the IR pathway and AD-like behavior is warranted.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Drug Combinations; Exenatide; Hypoglycemic Agents; Insulin; Male; Maze Learning; Mice; Mice, Inbred C57BL; Receptor, Insulin; Signal Transduction

The role of mitochondrial dysfunction has been well-documented in Alzheimer's disease (AD). Glucagon-like peptide 1 (GLP-1) receptor agonists are being utilized as neuroprotectants in the treatment of various neurological disorders, including AD. We conducted this study to explore the effects of exenatide (a GLP-1 receptor agonist) on β-amyloid plaque (Aβ)-induced cognitive impairment and mitochondrial dysfunction in 5xFAD transgenic mice. Spatial memory test showed that exenatide administration (100 μg/kg twice per day) prevented cognitive decline after 16 weeks of treatment. Aβ

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Brain; Cognitive Dysfunction; Disease Models, Animal; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hippocampus; Male; Memory; Mice; Mice, Inbred Strains; Mice, Transgenic; Mitochondria; Neuroprotective Agents; Plaque, Amyloid; Synapses

Alzheimer's disease (AD) is a multifactorial condition in which, along with amyloid-β (Aβ) and tau-related pathology, the synergistic activity of co-morbidity factors promote the onset and progression of the disease. Epidemiological evidence indicates that glucose intolerance, deficits in insulin secretion, or type-2 diabetes mellitus (T2DM) participate in increasing cognitive impairment or dementia risk. Insulin plays a pivotal role in the process as the hormone critically regulates brain functioning. GLP-1, the glucagon-like peptide 1, facilitates insulin signaling, regulates glucose homeostasis, and modulates synaptic plasticity. Exenatide is a synthetic GLP-1 analog employed in T2DM. However, exenatide has also been shown to affect the signaling of the brain-derived neurotrophic factor (BDNF), synaptic plasticity, and cognitive performances in animal models. In this study, we tested whether exenatide exerts neuroprotection in a preclinical AD model set to mimic the clinical complexity of the human disease. We investigated the effects of exenatide treatment in 3xTg-AD mice challenged with a high-fat diet (HFD). Endpoints of the study were variations in systemic metabolism, insulin and neurotrophic signaling, neuroinflammation, Aβ and tau pathology, and cognitive performances. Results of the study indicate that exenatide reverts the adverse changes of BDNF signaling and the neuroinflammation status of 3xTg-AD mice undergoing HFD without affecting systemic metabolism or promoting changes in cognitive performances.

Topics: Alzheimer Disease; Animals; Brain; Brain-Derived Neurotrophic Factor; Cognitive Dysfunction; Disease Models, Animal; Exenatide; Female; Glucagon-Like Peptide 1; Glucose Tolerance Test; Hypoglycemic Agents; Insulin; Insulin Resistance; Male; Mice; Neuroimmunomodulation; Neuronal Plasticity; Neuroprotective Agents; Signal Transduction

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Cell Survival; Disease Models, Animal; Down-Regulation; Enzyme Inhibitors; Exenatide; Glucagon-Like Peptide-1 Receptor; Male; Maze Learning; Memory Disorders; Mice; Mice, Transgenic; N-Acetylglucosaminyltransferases; Oncogene Protein v-akt; PC12 Cells; Peptides; Presenilin-1; Rats; RNA, Small Interfering; Signal Transduction; Venoms

The deposition of β-amyloid protein (Aβ) is one of the pathological characteristics of Alzheimer's disease (AD) and can disrupt circadian rhythm and impair learning and memory. Exendin-4, a therapeutic drug for type II diabetes mellitus (T2DM), exerts neuroprotective effects from the toxicity of Aβ. However, it is not clear whether Exendin-4 protects against Aβ-induced disruption of circadian rhythm. The neuroprotective effects of Exendin-4 have been studied using injection of Exendin-4 into the lateral ventricle and abdomen. However, these procedures are not suitable for clinical application.. First, male C57BL/6 mice received triple distilled water or Exendin-4 (0.1 nmol, 0.5 nmol) by intranasal administration. Exendin-4 levels were measured in the hippocampal samples using an ELISA Kit. Then, the study examined whether intranasal or hippocampal administration of Exendin-4 antagonized Aβ-induced disruption of circadian rhythm as well as impairment of learning and memory using the wheel-running activity assay and the Morris water maze test.. The study showed that intranasally administered Exendin-4 passed through the blood-brain barrier. Aβ31-35 given by intrahippocampal injection disrupted circadian rhythm and impaired learning and memory in C57BL/6 mice, and Exendin-4 given by nasal cavity or hippocampal administration ameliorated Aβ31-35-induced circadian rhythm disturbance of locomotor activity and impairment of learning and memory.. These findings provide pivotal experimental support for further study of the neuroprotective effects and clinical application of Exendin-4.

Topics: Administration, Intranasal; Alzheimer Disease; Amyloid beta-Peptides; Animals; Circadian Rhythm; Exenatide; Hippocampus; Male; Maze Learning; Memory; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Peptide Fragments; Peptides; Venoms

Impaired insulin signaling pathway in the brain in type 2 diabetes (T2D) is a risk factor for Alzheimer disease (AD). Glucagon-like peptide-1 (GLP-1) and its receptor agonist are widely used for treatment of T2D. Here we studied whether the effects of exendin-4 (EX-4), a long-lasting GLP-1 receptor agonist, could reduce the risk of AD in T2D.. Type 2 diabetes rats were injected with EX-4 for 28 consecutive days. Blood glucose and insulin levels, as well as GLP-1 and insulin in cerebrospinal fluid, were determined during the experiment. The phosphorylation level of tau at individual phosphorylation sites, the activities of phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT), and glycogen synthase kinase-3β (GSK-3β) were analyzed with Western blots.. The levels of phosphorylated tau protein at site Ser199/202 and Thr217 level in the hippocampus of T2D rats were found to be raised notably and evidently decreased after EX-4 intervention. In addition, brain insulin signaling pathway was ameliorated after EX-4 treatment, and this result was reflected by a decreased activity of PI3K/AKT and an increased activity of GSK-3β in the hippocampus of T2D rats as well as a rise in PI3K/AKT activity and a decline in GSK-3β activity after 4 weeks intervention of EX-4.. These results demonstrate that multiple days with EX-4 appears to prevent the hyperphosphorylation of AD-associated tau protein due to increased insulin signaling pathway in the brain. These findings support the potential use of GLP-1 for the prevention and treatment of AD in individuals with T2D.

Topics: Alzheimer Disease; Animals; Blood Glucose; Blotting, Western; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide-1 Receptor; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hippocampus; Hyperglycemia; Insulin; Insulin Resistance; Male; Peptides; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats, Sprague-Dawley; Receptors, Glucagon; Signal Transduction; tau Proteins; Venoms

Defective brain insulin signaling contributes to the cognitive deficits in Alzheimer's disease (AD). Amyloid-beta oligomers (AβOs), the primary neurotoxin implicated in AD, downregulate insulin signaling by impairing protein kinase B/AKT, thereby overactivating glycogen synthase kinase-3β. By this mechanism, AβOs may also impair axonal transport before tau-induced cytoskeletal collapse and cell death. Here, we demonstrate that a constitutively active form of protein kinase B/AKT prevents brain-derived neurotrophic factor (BDNF) transport defects in AβO-treated primary neurons from wild type (tau(+/+)) and tau knockout (tau(-/-)) mice. Remarkably, inhibition of glycogen synthase kinase-3β rescues BDNF transport defects independent of tau. Furthermore, exendin-4, an anti-diabetes agent, restores normal BDNF axonal transport by stimulating the glucagon-like peptide-1 receptor to activate the insulin pathway. Collectively, our findings indicate that normalized insulin signaling can both prevent and reverse BDNF transport defects in AβO-treated neurons. Ultimately, this work may reveal novel therapeutic targets that regulate BDNF trafficking, promote its secretion and uptake, and prolong neuronal survival during AD progression.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Axonal Transport; Brain-Derived Neurotrophic Factor; Cells, Cultured; Exenatide; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hippocampus; Hypoglycemic Agents; Insulin; Mice, Knockout; Neurons; Peptides; Proto-Oncogene Proteins c-akt; Signal Transduction; Stimulation, Chemical; tau Proteins; Venoms

Recent studies suggest a possible link between type 2 diabetes and Alzheimer's disease (AD). Glucogan-like peptide 1 (GLP-1) facilitates insulin release from pancreas under hyperglycemic conditions. In addition to its metabolic effects, GLP-1 and its long-lasting analogs, including exenatide can stimulate neurogenesis and improve cognition in rodent AD model. The aim of the present study was to investigate the effects of exenatide on hippocampal cellularity, cognitive performance and inflammation response in a rat model of AD. Fourteen rats were used to create AD model using intracerebroventricular (ICV) streptozotocin (STZ) infusion while 7 rats were administered 0.9% NaCl only (sham-operated group). Following stereotaxic surgery, STZ received rats were randomly distributed into two groups, and treated with either saline or exenatide 20 µgr/kg/day through intraperitoneally for two weeks. Then, cognitive performance (passive avoidance learning), brain tumor necrosis factor alpha (TNF-α) levels, choline acetyltransferase (ChAT) activity and hippocampal neuronal count were determined. While the brain TNF-α levels were significantly high in the saline-treated STZ group, exenatide treatment suppressed the increase in TNF-α levels. Saline-treated STZ group showed reduced ChAT activity compared to sham group. However, exenatide significantly preserved brain ChAT activity. The cognitive performance was also impaired in saline group while exenatide improved memory in rats. Moreover, exenatide treatment significantly prevented the decrease in hippocampal neurons. Overall, the results of the present study clearly indicated exenatide might have beneficial effects on impaired cognitive performance and hippocampal neuronal viability in AD by suppressing the inflammation response and increasing cholinergic activity.

Topics: Alzheimer Disease; Animals; Cell Count; Exenatide; Hippocampus; Hypoglycemic Agents; Infusions, Intraventricular; Male; Memory; Neurons; Peptides; Rats; Rats, Sprague-Dawley; Streptozocin; Tumor Necrosis Factor-alpha; Venoms

Recent studies have shown that type 2 diabetes mellitus (T2DM) is a risk factor for cognitive dysfunction or dementia. Insulin resistance is often associated with T2DM and can induce defective insulin signaling in the central nervous system as well as increase the risk of cognitive impairment in the elderly. Glucagone like peptide-1 (GLP-1) is an incretin hormone and, like GLP-1 analogs, stimulates insulin secretion and has been employed in the treatment of T2DM. GLP-1 and GLP-1 analogs also enhance synaptic plasticity and counteract cognitive deficits in mouse models of neuronal dysfunction and/or degeneration. In this study, we investigated the potential neuroprotective effects of long-term treatment with exenatide, a GLP-1 analog, in two animal models of neuronal dysfunction: the PS1-KI and 3xTg-AD mice. We found that exenatide promoted beneficial effects on short- and long-term memory performances in PS1-KI but not in 3xTg-AD animals. In PS1-KI mice, the drug increased brain lactate dehydrogenase activity leading to a net increase in lactate levels, while no effects were observed on mitochondrial respiration. On the contrary, exenatide had no effects on brain metabolism of 3xTg-AD mice. In summary, our data indicate that exenatide improves cognition in PS1-KI mice, an effect likely driven by increasing the brain anaerobic glycolysis rate.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Cognition Disorders; Diabetes Mellitus, Experimental; Disease Models, Animal; Electron Transport Complex IV; Exenatide; Female; Hypoglycemic Agents; L-Lactate Dehydrogenase; Lactic Acid; Male; Memory, Long-Term; Memory, Short-Term; Mice; Mice, Transgenic; Mitochondria; Peptides; tau Proteins; Venoms

Mild traumatic brain injury (mTBI) represents a major and increasing public health concern and is both the most frequent cause of mortality and disability in young adults and a chief cause of morbidity in the elderly. Albeit mTBI patients do not show clear structural brain defects and, generally, do not require hospitalization, they frequently suffer from long-lasting cognitive, behavioral, and emotional problems. No effective pharmaceutical therapy is available, and existing treatment chiefly involves intensive care management after injury. The diffuse neural cell death evident after mTBI is considered mediated by oxidative stress and glutamate-induced excitotoxicity. Prior studies of the long-acting GLP-1 receptor agonist, exendin-4 (Ex-4), an incretin mimetic approved for type 2 diabetes mellitus treatment, demonstrated its neurotrophic/protective activity in cellular and animal models of stroke, Alzheimer's and Parkinson's diseases, and, consequent to commonalities in mechanisms underpinning these disorders, Ex-4 was assessed in a mouse mTBI model. In neuronal cultures in this study, Ex-4 ameliorated H2O2-induced oxidative stress and glutamate toxicity. To evaluate in vivo translation, we administered steady-state Ex-4 (3.5 pM/kg/min) or saline to control and mTBI mice over 7 days starting 48 h prior to or 1 h post-sham or mTBI (30 g weight drop under anesthesia). Ex-4 proved well-tolerated and fully ameliorated mTBI-induced deficits in novel object recognition 7 and 30 days post-trauma. Less mTBI-induced impairment was evident in Y-maze, elevated plus maze, and passive avoidance paradigms, but when impairment was apparent Ex-4 induced amelioration. Together, these results suggest that Ex-4 may act as a neurotrophic/neuroprotective drug to minimize mTBI impairment.

Topics: Alzheimer Disease; Animals; Behavior, Animal; Brain; Brain Injuries; Cell Line; Disease Models, Animal; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Male; Memory; Mice; Neuroprotective Agents; Oxidative Stress; Peptides; Rats; Rats, Sprague-Dawley; Receptors, Glucagon; Recognition, Psychology; Trauma Severity Indices; Venoms

Traumatic brain injury (TBI) is a global problem reaching near epidemic numbers that manifests clinically with cognitive problems that decades later may result in dementias like Alzheimer's disease (AD). Presently, little can be done to prevent ensuing neurological dysfunctions by pharmacological means. Recently, it has become apparent that several CNS diseases share common terminal features of neuronal cell death. The effects of exendin-4 (Ex-4), a neuroprotective agent delivered via a subcutaneous micro-osmotic pump, were examined in the setting of mild TBI (mTBI). Utilizing a model of mTBI, where cognitive disturbances occur over time, animals were subjected to four treatments: sham; Ex-4; mTBI and Ex-4/mTBI. mTBI mice displayed deficits in novel object recognition, while Ex-4/mTBI mice performed similar to sham. Hippocampal gene expression, assessed by gene array methods, showed significant differences with little overlap in co-regulated genes between groups. Importantly, changes in gene expression induced by mTBI, including genes associated with AD were largely prevented by Ex-4. These data suggest a strong beneficial action of Ex-4 in managing secondary events induced by a traumatic brain injury.

Topics: Alzheimer Disease; Animals; Behavior, Animal; Brain Injuries; Cognition; Computational Biology; DNA, Complementary; Exenatide; Gene Expression; Glucagon-Like Peptide 1; Hippocampus; Male; Memory Disorders; Mice; Mice, Inbred ICR; Neuroprotective Agents; Peptides; Real-Time Polymerase Chain Reaction; Recognition, Psychology; RNA; Signal Transduction; Venoms

Growing evidence suggests that type 2 diabetes mellitus (DM) is associated with age-dependent Alzheimer's disease (AD), the latter of which has even been considered as type 3 diabetes. Several physiopathological features including hyperglycemia, oxidative stress, and dysfunctional insulin signaling relate DM to AD. In this study, high glucose-, oxidative stress-induced neuronal injury and intracerebroventricular-streptozotocin (ICV-STZ) animals as the possible models for diabetes-related AD were employed to investigate the effects of exendin-4 (Ex-4), a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist, on diabetes-associated Alzheimer-like changes as well as the molecular mechanisms involved. Our study demonstrated that GLP-1/Ex-4 could exert a protective effect against reduced viability of PC12 cells caused by high glucose and that this protective effect was mediated via the PI3-kinase pathway. In addition, GLP-1/Ex-4 ameliorated oxidative stress-induced injury in PC12 cells. In rat models, bilateral ICV-STZ administration was used to produce impaired insulin signaling in the brain. Fourteen days following ICV-STZ injection, rats treated with twice-daily Ex-4 had better learning and memory performance in the Morris water maze test compared with rats treated with saline. Additionally, histopathological evaluation confirmed the protective effects of Ex-4 treatment on hippocampal neurons against degeneration. Furthermore, we demonstrated that Ex-4 reversed ICV-STZ-induced tau hyperphosphorylation through downregulation of GSK-3β activity, a key kinase in both DM and AD. Our findings suggests that Ex-4 can protect neurons from diabetes-associated glucose metabolic dysregulation insults in vitro and from ICV-STZ insult in vivo, and that Ex-4 may prove of therapeutic value in the treatment of AD especially DM-related AD.

Topics: Alzheimer Disease; Animals; Blood Glucose; Cell Survival; Diabetes Mellitus, Experimental; Exenatide; Glucagon-Like Peptide 1; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hippocampus; Hypoglycemic Agents; Insulin; Male; Nerve Degeneration; Oxidative Stress; Peptides; Rats; Rats, Wistar; Venoms

Defective brain insulin signaling has been suggested to contribute to the cognitive deficits in patients with Alzheimer's disease (AD). Although a connection between AD and diabetes has been suggested, a major unknown is the mechanism(s) by which insulin resistance in the brain arises in individuals with AD. Here, we show that serine phosphorylation of IRS-1 (IRS-1pSer) is common to both diseases. Brain tissue from humans with AD had elevated levels of IRS-1pSer and activated JNK, analogous to what occurs in peripheral tissue in patients with diabetes. We found that amyloid-β peptide (Aβ) oligomers, synaptotoxins that accumulate in the brains of AD patients, activated the JNK/TNF-α pathway, induced IRS-1 phosphorylation at multiple serine residues, and inhibited physiological IRS-1pTyr in mature cultured hippocampal neurons. Impaired IRS-1 signaling was also present in the hippocampi of Tg mice with a brain condition that models AD. Importantly, intracerebroventricular injection of Aβ oligomers triggered hippocampal IRS-1pSer and JNK activation in cynomolgus monkeys. The oligomer-induced neuronal pathologies observed in vitro, including impaired axonal transport, were prevented by exposure to exendin-4 (exenatide), an anti-diabetes agent. In Tg mice, exendin-4 decreased levels of hippocampal IRS-1pSer and activated JNK and improved behavioral measures of cognition. By establishing molecular links between the dysregulated insulin signaling in AD and diabetes, our results open avenues for the investigation of new therapeutics in AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Animals; Antibodies, Monoclonal; Cells, Cultured; Exenatide; Female; Hippocampus; Humans; Hypoglycemic Agents; Infliximab; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Macaca fascicularis; Male; MAP Kinase Signaling System; Maze Learning; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Middle Aged; Neurons; Peptides; Phosphorylation; Protein Processing, Post-Translational; Rats; Venoms

Topics: Alzheimer Disease; Animals; Disease Models, Animal; Exenatide; Humans; Hypoglycemic Agents; Insulin Resistance; Peptides; Venoms

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Cognition Disorders; Exenatide; Female; Hippocampus; Humans; Hypoglycemic Agents; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Insulin-Like Growth Factor I; Male; Peptides; Venoms

Glucagon-like peptide-1(7-36)-amide (GLP-1) is an endogenous insulinotropic peptide that is secreted from the gastrointestinal tract in response to food. It enhances pancreatic islet beta-cell proliferation and glucose-dependent insulin secretion and lowers blood glucose and food intake in patients with type 2 diabetes mellitus. GLP-1 receptors, which are coupled to the cyclic AMP second messenger pathway, are expressed throughout the brains of rodents and humans. It was recently reported that GLP-1 and exendin-4, a naturally occurring, more stable analogue of GLP-1 that binds at the GLP-1 receptor, possess neurotrophic properties and can protect neurons against glutamate-induced apoptosis. We report here that GLP-1 can reduce the levels of amyloid-beta peptide (Abeta) in the brain in vivo and can reduce levels of amyloid precursor protein (APP) in cultured neuronal cells. Moreover, GLP-1 and exendin-4 protect cultured hippocampal neurons against death induced by Abeta and iron, an oxidative insult. Collectively, these data suggest that GLP-1 can modify APP processing and protect against oxidative injury, two actions that suggest a novel therapeutic target for intervention in Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Cell Death; Down-Regulation; Exenatide; Fetus; Glucagon; Glucagon-Like Peptide 1; Hippocampus; Iron; Male; Mice; Mice, Inbred Strains; Neurons; Neuroprotective Agents; Oxidative Stress; PC12 Cells; Peptide Fragments; Peptides; Protein Precursors; Rats; Rats, Sprague-Dawley; Venoms