Hsp90 activator Aha1 drives production of pathological tau aggregates
The microtubule-associated protein tau (MAPT, tau) forms neurotoxic aggregates that promote cognitive deficits in tauopathies, the most common of which is Alzheimer’s disease (AD). The 90-kDa heat shock protein (Hsp90) chaperone system affects the accumulation of these toxic tau species, which can b...
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Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 114; no. 36; pp. 9707 - 9712 |
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Main Authors | , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
National Academy of Sciences
05.09.2017
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Subjects | |
Online Access | Get full text |
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Summary: | The microtubule-associated protein tau (MAPT, tau) forms neurotoxic aggregates that promote cognitive deficits in tauopathies, the most common of which is Alzheimer’s disease (AD). The 90-kDa heat shock protein (Hsp90) chaperone system affects the accumulation of these toxic tau species, which can be modulated with Hsp90 inhibitors. However, many Hsp90 inhibitors are not blood–brain barrier-permeable, and several present associated toxicities. Here, we find that the cochaperone, activator of Hsp90 ATPase homolog 1 (Aha1), dramatically increased the production of aggregated tau. Treatment with an Aha1 inhibitor, KU-177, dramatically reduced the accumulation of insoluble tau. Aha1 colocalized with tau pathology in human brain tissue, and this association positively correlated with AD progression. Aha1 overexpression in the rTg4510 tau transgenic mouse model promoted insoluble and oligomeric tau accumulation leading to a physiological deficit in cognitive function. Overall, these data demonstrate that Aha1 contributes to tau fibril formation and neurotoxicity through Hsp90. This suggests that therapeutics targeting Aha1 may reduce toxic tau oligomers and slow or prevent neurodegenerative disease progression. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 1L.B.S., J.D.B., and D.Z. contributed equally to this work. 3Deceased November 25, 2016. Author contributions: L.B.S., B.S.J.B., and C.A.D. designed research; L.B.S., J.D.B., D.Z., L.E.S., P.K.S., Z.S., B.A.N., S.G., and L.J.B. performed research; B.A.N. and B.S.J.B. contributed new reagents/analytic tools; L.B.S., J.D.B., D.Z., J.M.W., J.J.S., and L.J.B. analyzed data; and L.B.S., J.M.W., J.K., L.J.B., and C.A.D. wrote the paper. Edited by Manu Sharma, Weill Cornell Medical College, New York, NY, and accepted by Editorial Board Member Gregory A. Petsko July 21, 2017 (received for review April 27, 2017) |
ISSN: | 0027-8424 1091-6490 |
DOI: | 10.1073/pnas.1707039114 |