Accelerated neurodegeneration through chaperone-mediated oligomerization of tau
Laura J. Blair, … , Nicole Berchtold, Chad A. Dickey
Laura J. Blair, … , Nicole Berchtold, Chad A. Dickey
Published September 3, 2013
Citation Information: J Clin Invest. 2013;123(10):4158-4169. https://doi.org/10.1172/JCI69003.
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Research Article Neuroscience

Accelerated neurodegeneration through chaperone-mediated oligomerization of tau

Abstract

Aggregation of tau protein in the brain is associated with a class of neurodegenerative diseases known as tauopathies. FK506 binding protein 51 kDa (FKBP51, encoded by FKBP5) forms a mature chaperone complex with Hsp90 that prevents tau degradation. In this study, we have shown that tau levels are reduced throughout the brains of Fkbp5–/– mice. Recombinant FKBP51 and Hsp90 synergized to block tau clearance through the proteasome, resulting in tau oligomerization. Overexpression of FKBP51 in a tau transgenic mouse model revealed that FKBP51 preserved the species of tau that have been linked to Alzheimer’s disease (AD) pathogenesis, blocked amyloid formation, and decreased tangle load in the brain. Alterations in tau turnover and aggregate structure corresponded with enhanced neurotoxicity in mice. In human brains, FKBP51 levels increased relative to age and AD, corresponding with demethylation of the regulatory regions in the FKBP5 gene. We also found that higher FKBP51 levels were associated with AD progression. Our data support a model in which age-associated increases in FKBP51 levels and its interaction with Hsp90 promote neurotoxic tau accumulation. Strategies aimed at attenuating FKBP51 levels or its interaction with Hsp90 have the potential to be therapeutically relevant for AD and other tauopathies.

Authors

Laura J. Blair, Bryce A. Nordhues, Shannon E. Hill, K. Matthew Scaglione, John C. O’Leary III, Sarah N. Fontaine, Leonid Breydo, Bo Zhang, Pengfei Li, Li Wang, Carl Cotman, Henry L. Paulson, Martin Muschol, Vladimir N. Uversky, Torsten Klengel, Elisabeth B. Binder, Rakez Kayed, Todd E. Golde, Nicole Berchtold, Chad A. Dickey

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Figure 2

FKBP51 and Hsp90 synergistically prevent tau degradation by the 20S proteasome.

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FKBP51 and Hsp90 synergistically prevent tau degradation by the 20S prot...
(A) Tau was incubated alone, with 20S proteasome, or with FKBP51 and 20S proteasome for 5 minutes. (B) Tau was incubated alone, with 20S proteasome, with FKBP51, and with Hsp90 with or without FKBP51 for 5 minutes. (C) Relative tau levels (± SEM) in each sample using 1 μM Hsp90. **P < 0.01, ***P < 0.001. (D) Tau levels (± SEM) following incubation with FKBP51 and Hsp90 in the presence of the 20S proteasome (green). Calculated tau levels (blue) from the addition of the results of tau preserved following incubation with Hsp90 and with the tau preserved following incubation with FKBP51 in the presence of the 20S proteasome. *P < 0.05. (E) FKBP51 was incubated with 100 μg Suc-LLVY-AMC and 20S proteasome for 5 minutes. OD readings (± SEM) were taken at 460 nm.