Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Neurosciences, Neurosciences & Neurology, A beta load, Alzheimer's disease, Lipid metabolism, gamma-Secretase, TUDCA, FAMILIAL ALZHEIMERS-DISEASE, PEPTIDE-INDUCED APOPTOSIS, RECEPTOR-RELATED PROTEIN, TISSUE-GROWTH-FACTOR, TAUROURSODEOXYCHOLIC ACID, APOLIPOPROTEIN-E, GAMMA-SECRETASE, URSODEOXYCHOLIC ACID, TRANSGENIC MICE, A-BETA, 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, 1109 Neurosciences, 1701 Psychology, 1702 Cognitive Sciences, Neurology & Neurosurgery, 3101 Biochemistry and cell biology, 3209 Neurosciences

Abstract:

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.