taurochenodeoxycholic-acid and Alzheimer-Disease

Bear bile has been used in Traditional Chinese Medicine for thousands of years due to its therapeutic potential and clinical applications. The tauroursodeoxycholic acid (TUDCA), one of the acids found in bear bile, is a hydrophilic bile acid and naturally produced in the liver by conjugation of taurine to ursodeoxycholic acid (UDCA). Several studies have shown that TUDCA has neuroprotective action in several models of neurodegenerative disorders (ND), including Alzheimer's disease, Parkinson's disease, and Huntington's disease, based on its potent ability to inhibit apoptosis, attenuate oxidative stress, and reduce endoplasmic reticulum stress in different experimental models of these illnesses. Our research extends the knowledge of the bile acid TUDCA actions in ND and the mechanisms and pathways involved in its cytoprotective effects on the brain, providing a novel perspective and opportunities for treatment of these diseases.

Topics: Alzheimer Disease; Animals; Apoptosis; Bile; Bile Acids and Salts; Endoplasmic Reticulum Stress; Humans; Medicine, Chinese Traditional; Neurodegenerative Diseases; Taurochenodeoxycholic Acid; Ursodeoxycholic Acid

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

Obesity and diabetes are well-established risk factors of Alzheimer's disease (AD). In the brains of patients with AD and model mice, diabetes-related factors have been implicated in the pathological changes of AD. However, the molecular mechanistic link between the peripheral metabolic state and AD pathophysiology have remained elusive. Endoplasmic reticulum (ER) stress is known as one of the major contributors to the metabolic abnormalities in obesity and diabetes. Interventions aimed at reducing ER stress have been shown to improve the systemic metabolic abnormalities, although their effects on the AD pathology have not been extensively studied.. We examined whether interventions targeting ER stress attenuate the obesity/diabetes-induced Aβ accumulation in brains. We also aimed to determine whether ER stress that took place in the peripheral tissues or central nervous system was more important in the Aβ neuropathology. Furthermore, we explored if age-related metabolic abnormalities and Aβ accumulation could be suppressed by reducing ER stress.. APP transgenic mice (A7-Tg), which exhibit Aβ accumulation in the brain, were used as a model of AD to analyze parameters of peripheral metabolic state, ER stress, and Aβ pathology in the brain. Intraperitoneal or intracerebroventricular administration of taurodeoxycholic acid (TUDCA), a chemical chaperone, was performed in high-fat diet (HFD)-fed A7-Tg mice for ~1 month, followed by analyses at 9 months of age. Mice fed a normal diet were treated with TUDCA by drinking water for 4 months and intraperitoneally for 1 month in parallel, and analyzed at 15 months of age.. Intraperitoneal administration of TUDCA suppressed ER stress in the peripheral tissues and ameliorated the HFD-induced obesity and insulin resistance. Concomitantly, Aβ levels in the brain were significantly reduced. In contrast, intracerebroventricular administration of TUDCA had no effect on the Aβ levels. Peripheral administration of TUDCA was also effective against the age-related obesity and insulin resistance, and markedly reduced amyloid accumulation.. Interventions that target peripheral ER stress might be beneficial therapeutic and prevention strategies against brain Aβ pathology associated with metabolic overload and aging.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antiviral Agents; Brain; Diet; Disease Models, Animal; Endoplasmic Reticulum Stress; Humans; Infusions, Intraventricular; Injections, Intraperitoneal; Mice; Mice, Transgenic; Taurochenodeoxycholic Acid

Alzheimer's disease (AD) is a neurodegenerative disorder and the major cause of dementia. According to predictions of the World Health Organization, more than 150 million people worldwide will suffer from dementia by 2050. An increasing number of studies have associated AD with type 2 diabetes mellitus (T2DM), since most of the features found in T2DM are also observed in AD, such as insulin resistance and glucose intolerance. In this sense, some bile acids have emerged as new therapeutic targets to treat AD and metabolic disorders. The taurine conjugated bile acid, tauroursodeoxycholic (TUDCA), reduces amyloid oligomer accumulation and improves cognition in APP/PS1 mice model of AD, and also improves glucose-insulin homeostasis in obese and type 2 diabetic mice. Herein, we investigated the effect of TUDCA upon glucose metabolism in streptozotocin-induced AD mice model (Stz). The Stz mice that received 300 mg/kg TUDCA during 10 days (Stz + TUDCA), showed improvement in glucose tolerance and insulin sensitivity, reduced fasted and fed glycemia, increased islet mass and β-cell area, as well as increased glucose-stimulated insulin secretion, compared with Stz mice that received only PBS. Stz + TUDCA mice also displayed lower neuroinflammation, reduced protein content of amyloid oligomer in the hippocampus, improved memory test and increased protein content of insulin receptor β-subunit in the hippocampus. In conclusion, TUDCA treatment enhanced glucose homeostasis in the streptozotocin-induced Alzheimer's disease mice model, pointing this bile acid as a good strategy to counteract glucose homeostasis disturbance in AD pathology.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Bile Acids and Salts; Blood Glucose; Cytokines; Disease Models, Animal; Glucose; Hippocampus; Inflammation; Insulin; Insulin-Secreting Cells; Male; Memory and Learning Tests; Mice; Mice, Inbred C57BL; Real-Time Polymerase Chain Reaction; Streptozocin; Taurochenodeoxycholic Acid

Calcium homeostasis plays a crucial role in neuronal development and disease. Calbindin-D. We used CaBP-9k knockout (KO) mice to investigate the roles of these gene in neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. We used anatomical and biochemical approaches to characterize functional abnormalities of the brain in the CaBP-9k KO mice.. We found that the brains of CaBP-9k KO mice have increased APP/β-amyloid, Tau, and α-synuclein accumulation and endoplasmic reticulum (ER) stress-induced apoptosis. Neurons deficient for these CaBP-9k had abnormal intracellular calcium levels and responses. ER stress inhibitor TUDCA reduced ER stress-induced apoptosis and restored ER stress- and apoptosis-related proteins expression to wild-type levels in CaBP-9k KO mice. Furthermore, treatment with TUDCA rescued the abnormal memory and motor behaviors exhibited by older CaBP-9k KO mice.. Our results suggest that a loss of CaBP-9k may contribute to the onset and progression of neurodegenerative diseases.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Animals; Apoptosis; Brain; Calbindins; Calcium; Cell Proliferation; Cells, Cultured; Endoplasmic Reticulum Stress; Maze Learning; Memory Disorders; Mice; Mice, Knockout; Motor Activity; Neurons; Parkinson Disease; Risk Factors; RNA, Small Interfering; tau Proteins; Taurochenodeoxycholic Acid

Alzheimer's disease (AD) is a neurodegenerative disorder hallmarked by the accumulation of extracellular amyloid-β (Aβ) peptide and intraneuronal hyperphosphorylated tau, as well as chronic neuroinflammation. Tauroursodeoxycholic acid (TUDCA) is an endogenous anti-apoptotic bile acid with potent neuroprotective properties in several experimental models of AD. We have previously reported the therapeutic efficacy of TUDCA treatment before amyloid plaque deposition in APP/PS1 double-transgenic mice. In the present study, we evaluated the protective effects of TUDCA when administrated after the onset of amyloid pathology. APP/PS1 transgenic mice with 7 months of age were injected intraperitoneally with TUDCA (500 mg/kg) every 3 days for 3 months. TUDCA treatment significantly attenuated Aβ deposition in the brain, with a concomitant decrease in Aβ₁₋₄₀ and Aβ₁₋₄₂ levels. The amyloidogenic processing of amyloid precursor protein was also reduced, indicating that TUDCA interferes with Aβ production. In addition, TUDCA abrogated GSK3β hyperactivity, which is highly implicated in tau hyperphosphorylation and glial activation. This effect was likely dependent on the specific activation of the upstream kinase, Akt. Finally, TUDCA treatment decreased glial activation and reduced proinflammatory cytokine messenger RNA expression, while partially rescuing synaptic loss. Overall, our results suggest that TUDCA is a promising therapeutic strategy not only for prevention but also for treatment of AD after disease onset.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Cholagogues and Choleretics; Cytokines; Disease Models, Animal; Gene Expression; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Inflammation Mediators; Mice, Transgenic; Molecular Targeted Therapy; Neuroprotective Agents; Presenilin-1; Protein Aggregation, Pathological; RNA, Messenger; tau Proteins; Taurochenodeoxycholic Acid

The unfolded protein response (UPR) is activated in neurodegenerative tauopathies such as Alzheimer's disease (AD) in close connection with early stages of tau pathology. Metabolic disturbances are strongly associated with increased risk for AD and are a potent inducer of the UPR. Here, we demonstrate that metabolic stress induces the phosphorylation of endogenous tau via activation of the UPR. Strikingly, upon restoration of the metabolic homeostasis, not only the levels of the UPR markers pPERK, pIRE1α and BiP, but also tau phosphorylation are reversed both in cell models as well as in torpor, a physiological hypometabolic model in vivo. Intervention in the UPR using the global UPR inhibitor TUDCA or a specific small-molecule inhibitor of the PERK signaling pathway, inhibits the metabolic stress-induced phosphorylation of tau. These data support a role for UPR-mediated tau phosphorylation as part of an adaptive response to metabolic stress. Failure to restore the metabolic homeostasis will lead to prolonged UPR activation and tau phosphorylation, and may thus contribute to AD pathogenesis. We demonstrate that the UPR is functionally involved in the early stages of tau pathology. Our data indicate that targeting of the UPR may be employed for early intervention in tau-related neurodegenerative diseases.

Topics: Alzheimer Disease; Animals; Cell Line, Tumor; Cerebral Cortex; Cold Temperature; Corpus Striatum; Cricetinae; Deoxyglucose; eIF-2 Kinase; Endoribonucleases; Hippocampus; Humans; Phosphorylation; Protein Serine-Threonine Kinases; Signal Transduction; Stress, Physiological; tau Proteins; Taurochenodeoxycholic Acid; Tunicamycin; Unfolded Protein Response

Synapses are considered the earliest site of Alzheimer's disease (AD) pathology, where synapse density is reduced, and synaptic loss is highly correlated with cognitive impairment. Tauroursodeoxycholic acid (TUDCA) has been shown to be neuroprotective in several models of AD, including neuronal exposure to amyloid β (Aβ) and amyloid precursor protein (APP)/presenilin 1 (PS1) double-transgenic mice. Here, we show that TUDCA modulates synaptic deficits induced by Aβ in vitro. Specifically, TUDCA reduced the downregulation of the postsynaptic marker postsynaptic density-95 (PSD-95) and the decrease in spontaneous miniature excitatory postsynaptic currents (mEPSCs) frequency, while increasing the number of dendritic spines. This contributed to the induction of more robust and synaptically efficient neurons, reflected in inhibition of neuronal death. In vivo, TUDCA treatment of APP/PS1 mice abrogated the decrease in PSD-95 reactivity in the hippocampus. Taken together, these results expand the neuroprotective role of TUDCA to a synaptic level, further supporting the use of this molecule as a potential therapeutic strategy for the prevention and treatment of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Cell Death; Cerebral Cortex; Disease Models, Animal; Down-Regulation; Hippocampus; Mice; Mice, Transgenic; Neurons; Neuroprotective Agents; Presenilin-1; Rats; Rats, Wistar; Synapses; Taurochenodeoxycholic Acid

Alzheimer's disease (AD) is a neurodegenerative disease hallmarked by extracellular Aβ(1-42) containing plaques, and intracellular neurofibrillary tangles (NFT) containing hyperphosphorylated tau protein. Progressively, memory deficits and cognitive disabilities start to occur as these hallmarks affect hippocampus and frontal cortex, regions highly involved in memory. Connective tissue growth factor (CTGF) expression, which is high in the vicinity of Aβ plaques and NFTs, was found to influence γ-secretase activity, the molecular crux in Aβ(1-42) production. Tauroursodeoxycholic acid (TUDCA) is an endogenous bile acid that downregulates CTGF expression in hepatocytes and has been shown to possess therapeutic efficacy in neurodegenerative models. To investigate the possible in vivo therapeutic effects of TUDCA, we provided 0.4% TUDCA-supplemented food to APP/PS1 mice, a well-established AD mouse model. Six months of TUDCA supplementation prevented the spatial, recognition and contextual memory defects observed in APP/PS1 mice at 8 months of age. Furthermore, TUDCA-supplemented APP/PS1 mice displayed reduced hippocampal and prefrontal amyloid deposition. These effects of TUDCA supplementation suggest a novel mechanistic route for Alzheimer therapeutics.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Amyloidogenic Proteins; Animals; Behavior, Animal; Cholagogues and Choleretics; Cognition Disorders; Dietary Supplements; Disease Models, Animal; Male; Mice; Mice, Transgenic; Presenilin-1; Taurochenodeoxycholic Acid

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by accumulation of amyloid-β (Aβ) peptide in the hippocampus and frontal cortex of the brain, leading to progressive cognitive decline. The endogenous bile acid tauroursodeoxycholic acid (TUDCA) is a strong neuroprotective agent in several experimental models of disease, including neuronal exposure to Aβ. Nevertheless, the therapeutic role of TUDCA in AD pathology has not yet been ascertained. Here we report that feeding APP/PS1 double-transgenic mice with diet containing 0.4 % TUDCA for 6 months reduced accumulation of Aβ deposits in the brain, markedly ameliorating memory deficits. This was accompanied by reduced glial activation and neuronal integrity loss in TUDCA-fed APP/PS1 mice compared to untreated APP/PS1 mice. Furthermore, TUDCA regulated lipid-metabolism mediators involved in Aβ production and accumulation in the brains of transgenic mice. Overall amyloidogenic APP processing was reduced with TUDCA treatment, in association with, but not limited to, modulation of γ-secretase activity. Consequently, a significant decrease in Aβ(1-40) and Aβ(1-42) levels was observed in both hippocampus and frontal cortex of TUDCA-treated APP/PS1 mice, suggesting that chronic feeding of TUDCA interferes with Aβ production, possibly through the regulation of lipid-metabolism mediators associated with APP processing. These results highlight TUDCA as a potential therapeutic strategy for the prevention and treatment of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Astrocytes; Bile Acids and Salts; Brain; Cognition Disorders; DNA-Binding Proteins; Humans; Lipid Metabolism; Mice; Mice, Transgenic; Microglia; Nerve Tissue Proteins; Neurons; Nuclear Proteins; Presenilin-1; Protein Processing, Post-Translational; Synucleins; Taurochenodeoxycholic Acid

Apolipoprotein (apo) E4 is a major genetic risk factor for a wide spectrum of inflammatory metabolic diseases, including atherosclerosis, diabetes, and Alzheimer disease. This study compared diet-induced adipose tissue inflammation as well as functional properties of macrophages isolated from human APOE3 and APOE4 mice to identify the mechanism responsible for the association between apoE4 and inflammatory metabolic diseases. The initial study confirmed previous reports that APOE4 gene replacement mice were less sensitive than APOE3 mice to diet-induced body weight gain but exhibited hyperinsulinemia, and their adipose tissues were similarly inflamed as those in APOE3 mice. Peritoneal macrophages isolated from APOE4 mice were defective in efferocytosis compared with APOE3 macrophages. Increased cell death was also observed in APOE4 macrophages when stimulated with LPS or oxidized LDL. Western blot analysis of cell lysates revealed that APOE4 macrophages displayed elevated JNK phosphorylation indicative of cell stress even under basal culturing conditions. Significantly higher cell stress due mainly to potentiation of endoplasmic reticulum (ER) stress signaling was also observed in APOE4 macrophages after LPS and oxidized LDL activation. The defect in efferocytosis and elevated apoptosis sensitivity of APOE4 macrophages was ameliorated by treatment with the ER chaperone tauroursodeoxycholic acid. Taken together, these results showed that apoE4 expression causes macrophage dysfunction and promotes apoptosis via ER stress induction. The reduction of ER stress in macrophages may be a viable option to reduce inflammation and inflammation-related metabolic disorders associated with the apoE4 polymorphism.

Topics: Adipose Tissue; Alzheimer Disease; Animals; Apolipoprotein E3; Apolipoprotein E4; Apoptosis; Cells, Cultured; Cholagogues and Choleretics; Endoplasmic Reticulum Stress; Gene Expression Regulation; Hyperinsulinism; Inflammation; Lipopolysaccharides; Lipoproteins, LDL; Macrophages, Peritoneal; MAP Kinase Kinase 4; Metabolic Diseases; Mice; Mice, Transgenic; Phosphorylation; Polymorphism, Genetic; Signal Transduction; Taurochenodeoxycholic Acid

The potential role of apoptosis in Alzheimer's disease (AD) has been an area of intense research in recent years. Ursodeoxycholic acid (UDCA) and its taurine-conjugate, tauroursodeoxycholic acid (TUDCA) are endogenous bile acids that act as potent inhibitors of apoptosis. Their therapeutic effects have been tested in many experimental pathological conditions, including neurological disorders, such as AD. TUDCA regulates precise transcriptional and post-transcriptional events that impact mitochondrial function in neurons. TUDCA not only stabilizes the mitochondrial membrane and prevents Bax translocation, inhibiting the release of cytochrome c and the activation of caspases, but also interferes with upstream factors, including cell cycle-related proteins. In addition, TUDCA is capable of inducing survival pathways. Here, we review the role of apoptosis in AD and discuss the therapeutic potential of TUDCA in treating this disease.

Topics: Alzheimer Disease; Animals; Apoptosis; Bile Acids and Salts; Cell Cycle Proteins; Humans; Models, Biological; Taurochenodeoxycholic Acid; Ursodeoxycholic Acid

Early onset familial Alzheimer's disease (FAD) is linked to autosomal dominant mutations in the amyloid precursor protein (APP) and presenilin 1 and 2 (PS1 and PS2) genes. These are critical mediators of total amyloid beta-peptide (Abeta) production, inducing cell death through uncertain mechanisms. Tauroursodeoxycholic acid (TUDCA) modulates exogenous Abeta-induced apoptosis by interfering with E2F-1/p53/Bax. Here, we used mouse neuroblastoma cells that express either wild-type APP, APP with the Swedish mutation (APPswe), or double-mutated human APP and PS1 (APPswe/DeltaE9), all exhibiting increased Abeta production and aggregation. Cell viability was decreased in APPswe and APPswe/DeltaE9 but was partially reversed by z-VAD.fmk. Nuclear fragmentation and caspase 2, 6 and 8 activation were also readily detected. TUDCA reduced nuclear fragmentation as well as caspase 2 and 6, but not caspase 8 activities. p53 activity, and Bcl-2 and Bax changes, were also modulated by TUDCA. Overexpression of p53, but not mutant p53, in wild-type and mutant neuroblastoma cells was sufficient to induce apoptosis, which, in turn, was reduced by TUDCA. In addition, inhibition of the phosphatidylinositide 3'-OH kinase pathway reduced TUDCA protection against p53-induced apoptosis. In conclusion, FAD mutations are associated with the activation of classical apoptotic pathways. TUDCA reduces p53-induced apoptosis and modulates expression of Bcl-2 family.

Topics: Alzheimer Disease; Amino Acid Chloromethyl Ketones; Amyloid beta-Protein Precursor; Animals; Antiviral Agents; Apoptosis; bcl-2-Associated X Protein; Blotting, Western; Caspases; Cell Line, Tumor; Cysteine Proteinase Inhibitors; Enzyme Activation; Humans; In Situ Nick-End Labeling; Membrane Proteins; Mice; Mutation; Neuroblastoma; Presenilin-1; Presenilin-2; Proto-Oncogene Proteins c-bcl-2; Taurochenodeoxycholic Acid; Transfection; Tumor Suppressor Protein p53