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In neurodegenerative diseases like Alzheimer's disease (AD), tau is hyperphosphorylated and forms aggregates and neurofibrillary tangles in affected neurons. Autophagy is critical to clear the aggregates of disease-associated proteins and is often altered in patients and animal models of AD. Because mechanistic target of rapamycin (mTOR) negatively regulates autophagy and is hyperactive in the brains of patients with AD, mTOR is an attractive therapeutic target for AD. However, pharmacological strategies to increase autophagy by targeting mTOR inhibition cause various side effects. Therefore, autophagy activation mediated by non-mTOR pathways is a new option for autophagy-based AD therapy. Here, we report that pimozide activates autophagy to rescue tau pathology in an AD model. Pimozide increased autophagic flux through the activation of the AMPK-Unc-51 like autophagy activating kinase 1 (ULK1) axis, but not of mTOR, in neuronal cells, and this function was independent of dopamine D2 receptor inhibition. Pimozide reduced levels of abnormally phosphorylated tau aggregates in neuronal cells. Further, daily intraperitoneal (i.p.) treatment of pimozide led to a recovery from memory deficits of TauC3 mice expressing a caspase-cleaved form of tau. In the brains of these mice, we found increased phosphorylation of AMPK1 and ULK1, and reduced levels of the soluble oligomers and NP40-insoluble aggregates of abnormally phosphorylated tau. Together, these results suggest that pimozide rescues memory impairments in TauC3 mice and reduces tau aggregates by increasing autophagic flux through the mTOR-independent AMPK-ULK1 axis.
Pubmed ID: 28632947 RIS Download
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This polyclonal targets PPP1CC
View all literature mentionsThis polyclonal targets PP1alpha (C-19)
View all literature mentionsThis unknown targets mTOR
View all literature mentionsThis polyclonal targets Phospho-mTOR (Ser2448)
View all literature mentionsThis monoclonal targets AMPK (D63G4)
View all literature mentionsThis polyclonal targets Phospho-AMPKα (Thr172)
View all literature mentionsThis monoclonal targets Phospho-ULK1 (Ser555)
View all literature mentionsThis polyclonal targets Phospho-S6 Ribosomal Protein (Ser235/236)
View all literature mentionsThis polyclonal targets p70 S6 Kinase
View all literature mentionsThis monoclonal targets p70 S6 Kinase, phospho (Thr389)
View all literature mentionsThis unknown targets p62/SQSTM1
View all literature mentionsThis monoclonal targets Tau (Cleaved Asp421, Asp422)
View all literature mentionsThis monoclonal targets Tau
View all literature mentionsStatistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.
View all literature mentionsCell line SH-SY5Y is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line HeLa is a Cancer cell line with a species of origin Homo sapiens
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