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 3

FKBP51 and Hsp90 combine to produce oligomeric tau structures.

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FKBP51 and Hsp90 combine to produce oligomeric tau structures. (A) CD sp...
(A) CD spectra of tau, FKBP51, and Hsp90 recombinant protein. CD spectra were obtained at protein concentrations of 10 μM tau, 2 μM FKBP51, and 3 μM Hsp90 in 10 mM sodium phosphate buffer (pH 7.5) at room temperature. (B) CD spectra readout of tau incubated with FKBP51, Hsp90, or both (solid lines). Calculated (calc) CD spectra (dashed lines) from the addition of each protein’s spectra shows what the readout would display if there were not protein interactions. Measurements of tau filament formation were monitored daily for 6 days, with a reading taken at least every 16 hours. (C) Tau fibril assembly was measured (± SEM) using DLS in the presence of FKBP51, Hsp90, and both combined. DLS measurements of tau filament formation were monitored daily for 6 days, with a reading taken at least every 16 hours. (D) Tau was stained with Thioflavin T (ThT) to show β-pleated sheet aggregation after 6 days of incubation alone or with FKBP51, Hsp90, or both combined (± SEM). ***P < 0.0001. (E) Atomic force microscopy images of tau multimers. The product of the DLS was imaged using atomic force microscopy for conformation. Both height (black) and amplitude (gray) images are shown. Scale bar: 0.5 μm. (F) Recombinant proteins were applied to a dot blot after 6 days, with heparin incubation at a ratio of 35 parts tau to 1 part chaperone combination. This was probed with T22 and H150 (total tau) antibodies.