title: TUDCA, a bile acid, attenuates amyloid precursor protein processing and amyloid-β deposition in APP/PS1 mice.
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.
authors.affiliation: Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon, Lisbon, 1649-003, Portugal.
authors.forename: Ana F
authors.initials: AF
authors.lastname: Nunes
authors.forename: Joana D
authors.initials: JD
authors.lastname: Amaral
authors.forename: Adrian C
authors.initials: AC
authors.lastname: Lo
authors.forename: Maria B
authors.initials: MB
authors.lastname: Fonseca
authors.forename: Ricardo J S
authors.initials: RJ
authors.lastname: Viana
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Callaerts-Vegh
authors.forename: Rudi
authors.initials: R
authors.lastname: D'Hooge
authors.forename: Cecília M P
authors.initials: CM
authors.lastname: Rodrigues
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001647:Bile Acids and Salts / Q000494:pharmacology* / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003072:Cognition Disorders / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D004268:DNA-Binding Proteins; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D053764:Presenilin-1 / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D051843:Synucleins / Q000378:metabolism; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001647:Bile Acids and Salts; D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; C492380:NeuN protein, mouse; D009687:Nuclear Proteins; D053764:Presenilin-1; D051843:Synucleins; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine