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 4

FKBP51 overexpression by viral vector in rTg4510 mice preserves tau.

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FKBP51 overexpression by viral vector in rTg4510 mice preserves tau. (A)...
(A) GFP or FKBP51 was overexpressed in the HPC of rTg4510 mice using an AAV9 vector. Scale bar: 2,000 μm; 50 μm (inset). Original magnification, ×63 (inset). (B) Total tau (± SEM) was measured using ImageJ in neurons expressing FKBP51 or GFP. At least 15 images were taken per animal. ***P < 0.0001. (C) Representative images FKBP51- and GFP-expressing neurons (arrows) (original magnification, ×63) using antibodies toward GFP (green), FKBP51 (green), total Tau (red), and NeuN (blue). Scale bar: 50 μm. (D) Tissue from injected mice was stained for pT231 tau. pT231-positive area (± SEM) was measured per CA3. *P = 0.0463. Representative sections are shown. Scale bar: 2,000 μm; 200 μm (inset). Original magnification, ×10 (inset). (E) T22 oligomeric tau (± SEM) was measured in the CA3 region of FKBP51- and GFP-overexpressing mice. *P = 0.0176. Scale bar: 2,000 μm; 200 μm (inset). Original magnification, ×10 (inset). (F) Representative Western blot of brain homogenate from FKBP51- or GFP AAV–injected mice immunoblotted with FKBP51, pT231, H150 (total tau), and GAPDH. T22 antibody on complimentary dot blot. (G) Quantification of Western blots (± SEM). #P = 0.03, pT231; *P = 0.05, H150 (total tau); **P = 0.002, T22.