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A high‐throughput drug screen identifies berberine as a potent inducer of tau clearance
Author(s) -
van der Kant Rik,
Langness Vanessa,
Rissman Robert A.,
Goldstein Lawrence S.B.
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.044798
Subject(s) - berberine , alkaloid , pharmacology , ampk , induced pluripotent stem cell , chemistry , biology , biochemistry , phosphorylation , embryonic stem cell , protein kinase a , gene , stereochemistry
Background Berberine is an isoquinoline alkaloid derived from plants of the Berberis genus. Berberine has been clinically evaluated for Type 2 Diabetes and has been shown to reduce blood glucose levels and improve lipid metabolism. Through an unbiased high‐throughput drug screen in human induced pluripotent stem cell‐derived neurons, we recently discovered that berberine also potently reduces Tau pathology in Alzheimer’s disease (AD) neurons. Method We used human iPSC‐derived neuronal models and Tau‐transgenic mice to uncover the mode of action by which Berberine reduces Tau pathology. Result We show that berberine acts on mitochondrial respiration and induces a switch in neuronal metabolism from oxidative phosphorylation to glycolysis. This switch induced by berberine, and mimicked by other mitochondrial targeting drugs such as metformin, drives activation of the energy sensor AMPK and leads to downstream activation of autophagosomal and proteasomal clearance of Tau. We show that berberine potently reduce Tau levels in a large panel of iPSC‐derived neuron from AD patients, as well as in Tau‐transgenic mice. Conclusion Berberine is a well‐tolerated oral agent that passes the blood‐brain‐barrier. Our data indicate that berberine could be repurposed for the treatment of AD and frontotemporal dementia with Tau pathology (FTD‐Tau).