Author:

Keywords:

Amyloid-beta, Amyloid precursor protein, APP/PS1 mice, Glycogen synthase kinase beta, Gliosis, Tau, TUDCA, Science & Technology, Life Sciences & Biomedicine, Geriatrics & Gerontology, Neurosciences, Neurosciences & Neurology, PEPTIDE-INDUCED APOPTOSIS, TRANSGENIC MOUSE MODELS, LONG-TERM POTENTIATION, ALZHEIMERS-DISEASE, PRECURSOR PROTEIN, SIGNALING PATHWAY, BILE-ACID, IN-VIVO, COGNITIVE IMPAIRMENT, HUNTINGTONS-DISEASE, Amyloid-β, Glycogen synthase kinase β, 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, Taurochenodeoxycholic Acid, tau Proteins, 1103 Clinical Sciences, 1109 Neurosciences, Neurology & Neurosurgery, 3209 Neurosciences, 5202 Biological psychology

Abstract:

Alzheimer’s disease (AD) is a neurodegenerative disorder hallmarked by the accumulation of extracellular amyloid-b (Ab) 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 Ab deposition in the brain, with a concomitant decrease in Ab1-40 and Ab1-42 levels. The amyloidogenic processing of amyloid precursor protein was also reduced, indicating that TUDCA interferes with Ab production. In addition, TUDCA abrogated GSK3b 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.