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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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 1

Tau expression is decreased in the Fkbp5–/– mice and associates with FKBP51 in the AD brain.

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Tau expression is decreased in the Fkbp5–/– mice and associates with FKB...
Representative images of brain tissue from (A) wild-type and (B) Fkbp5–/– mice stained for pT231 tau and corresponding sections without primary (no primary). Scale bar: 2,000 μm. (C) Quantification of pT231 stain (± SEM). **P = 0.0097. (D) Representative Western blot of brain homogenates from Fkbp5–/– mice probed for CP13 (pS202/pT205), Tau 12 (total tau), pT231 tau, H150 (total tau), and GAPDH. (E) Quantification of duplicate Western blots (± SEM). *P < 0.05 for CP13, Tau 12 (total tau), and H150 (total tau); ***P < 0.001 for pT231. (F) Fluorescent micrograph of human cortex stained with FKBP51, PHF1 (pS396/pS404), and Neurotrace (neuronal nuclei) antibodies (original magnification, ×60). Scale bar: 50 μm.