The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteins
Chad A. Dickey, … , Francis Burrows, Leonard Petrucelli
Chad A. Dickey, … , Francis Burrows, Leonard Petrucelli
Published March 1, 2007
Citation Information: J Clin Invest. 2007;117(3):648-658. https://doi.org/10.1172/JCI29715.
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Research Article

The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteins

Abstract

A primary pathologic component of Alzheimer’s disease (AD) is the formation of neurofibrillary tangles composed of hyperphosphorylated tau (p-tau). Expediting the removal of these p-tau species may be a relevant therapeutic strategy. Here we report that inhibition of Hsp90 led to decreases in p-tau levels independent of heat shock factor 1 (HSF1) activation. A critical mediator of this mechanism was carboxy terminus of Hsp70–interacting protein (CHIP), a tau ubiquitin ligase. Cochaperones were also involved in Hsp90-mediated removal of p-tau, while those of the mature Hsp90 refolding complex prevented this effect. This is the first demonstration to our knowledge that blockade of the refolding pathway promotes p-tau turnover through degradation. We also show that peripheral administration of a novel Hsp90 inhibitor promoted selective decreases in p-tau species in a mouse model of tauopathy, further suggesting a central role for the Hsp90 complex in the pathogenesis of tauopathies. When taken in the context of known high-affinity Hsp90 complexes in affected regions of the AD brain, these data implicate a central role for Hsp90 in the development of AD and other tauopathies and may provide a rationale for the development of novel Hsp90-based therapeutic strategies.

Authors

Chad A. Dickey, Adeela Kamal, Karen Lundgren, Natalia Klosak, Rachel M. Bailey, Judith Dunmore, Peter Ash, Sareh Shoraka, Jelena Zlatkovic, Christopher B. Eckman, Cam Patterson, Dennis W. Dickson, N. Stanley Nahman Jr., Michael Hutton, Francis Burrows, Leonard Petrucelli

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Figure 8

EC102 crosses the blood-brain barrier and acts as an Hsp90 inhibitor, decreasing p-tau levels in a mouse model of tauopathy.

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EC102 crosses the blood-brain barrier and acts as an Hsp90 inhibitor, de...
(A and B) Mice (n = 7 per group) were injected i.p. with either 200 mg/kg EC102 or equivalent vehicle once daily for 7 days. Following the final injection, 5 mice were killed within 1 hour, the 2 remaining mice were harvested 24 hours later, and their brain homogenates were assessed by Western blot (A) and those of the 5 animals harvested after 1 hour were quantitated by densitometry normalized to GAPDH (B). Hsp70 levels showed a significant increase compared with vehicle-treated mice that persisted for 24 hours. Conversely, Hsp90 levels were significantly reduced only 1 hour after EC102 administration, but were indistinguishable from vehicle-treated animals within 24 hours. Values represent optical density ± SD. (C and D) Two cohorts of four 13- to 14-month-old Htau mice were injected i.p. with either EC102 or vehicle as above, all tissue was harvested 24 hours following the final injection, and Western blot (C) and densitometric quantitation for total tau (D) were performed. Dramatic reductions in phosphorylated S396/S404 and S202/T205 immunoreactivity in EC102-treated mice were observed. Hsp70 levels were significantly elevated in EC102-treated animals. Only the high–molecular weight species of tau (60–65 kDa), presumably p-tau species, were reduced by EC102 treatment; normal tau species (45–55 kDa) remained unaffected. Levels of Hsp90 clients Cdk5 and Akt were unaltered by Hsp90 inhibition. Error bars represent SD. *P < 0.05; **P < 0.001 versus vehicle.