Prolonged tau clearance and stress vulnerability rescue by pharmacological activation of autophagy in tauopathy neurons

M. Catarina Silva, Ghata A. Nandi, Sharon Tentarelli, Ian K. Gurrell, Tanguy Jamier, Diane Lucente, Bradford C. Dickerson, Dean G. Brown, Nicholas J. Brandon and Stephen J. Haggarty ()
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M. Catarina Silva: Massachusetts General Hospital and Harvard Medical School
Ghata A. Nandi: Massachusetts General Hospital and Harvard Medical School
Sharon Tentarelli: Chemistry, Oncology R&D, AstraZeneca
Ian K. Gurrell: Neuroscience, BioPharmaceuticals R&D, AstraZeneca
Tanguy Jamier: Neuroscience, BioPharmaceuticals R&D, AstraZeneca
Diane Lucente: Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital and Harvard Medical School
Bradford C. Dickerson: Massachusetts General Hospital and Harvard Medical School
Dean G. Brown: AstraZeneca
Nicholas J. Brandon: AstraZeneca
Stephen J. Haggarty: Massachusetts General Hospital and Harvard Medical School

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: Abstract Tauopathies are neurodegenerative diseases associated with accumulation of abnormal tau protein in the brain. Patient iPSC-derived neuronal cell models replicate disease-relevant phenotypes ex vivo that can be pharmacologically targeted for drug discovery. Here, we explored autophagy as a mechanism to reduce tau burden in human neurons and, from a small-molecule screen, identify the mTOR inhibitors OSI-027, AZD2014 and AZD8055. These compounds are more potent than rapamycin, and robustly downregulate phosphorylated and insoluble tau, consequently reducing tau-mediated neuronal stress vulnerability. MTORC1 inhibition and autophagy activity are directly linked to tau clearance. Notably, single-dose treatment followed by washout leads to a prolonged reduction of tau levels and toxicity for 12 days, which is mirrored by a sustained effect on mTORC1 inhibition and autophagy. This new insight into the pharmacodynamics of mTOR inhibitors in regulation of neuronal autophagy may contribute to development of therapies for tauopathies.

Date: 2020
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DOI: 10.1038/s41467-020-16984-1

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