title: Amyloid-β pathology is attenuated by tauroursodeoxycholic acid treatment in APP/PS1 mice after disease onset.
abstract: 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.
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Dionísio
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal. Electronic address: jamaral@ff.ul.pt.
authors.forename: Joana D
authors.initials: JD
authors.lastname: Amaral
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.
authors.forename: Maria F
authors.initials: MF
authors.lastname: Ribeiro
authors.affiliation: Laboratory of Biological Psychology and Leuven Institute of Neuroscience and Disease (LIND), University of Leuven, Leuven, Belgium.
authors.forename: Adrian C
authors.initials: AC
authors.lastname: Lo
authors.affiliation: Laboratory of Biological Psychology and Leuven Institute of Neuroscience and Disease (LIND), University of Leuven, Leuven, Belgium.
authors.forename: Rudi
authors.initials: R
authors.lastname: D'Hooge
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal. Electronic address: cmprodrigues@ff.ul.pt.
authors.forename: Cecília M P
authors.initials: CM
authors.lastname: Rodrigues
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D002756:Cholagogues and Choleretics; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D018836:Inflammation Mediators / Q000378:metabolism; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D018696:Neuroprotective Agents; D053764:Presenilin-1 / Q000235:genetics; D066263:Protein Aggregation, Pathological / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control; D012333:RNA, Messenger / Q000378:metabolism; D013655:Taurochenodeoxycholic Acid / Q000008:administration & dosage* / Q000494:pharmacology; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002756:Cholagogues and Choleretics; D016207:Cytokines; D018836:Inflammation Mediators; C558298:Mapt protein, mouse; D018696:Neuroprotective Agents; D053764:Presenilin-1; D012333:RNA, Messenger; C580804:presenilin 1, mouse; D016875:tau Proteins; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3
keywords: APP/PS1 mice; Amyloid precursor protein; Amyloid-β; Gliosis; Glycogen synthase kinase β; TUDCA; Tau