Hsp90 co-chaperones, FKBP52 and Aha1, promote tau pathogenesis in aged wild-type mice

Acta Neuropathologica Communications

Marangelie Criado-Marrero¹  David Beaulieu-Abdelahad¹  Jeremy D. Baker¹  Danielle M. Blazier¹  Lauren A. Gould¹  Niat T. Gebru¹  Laura J. Blair² 

[1] USF Health Byrd Alzheimer’s Institute, University of South Florida, 33613, Tampa, FL, USA;Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, 33620, Tampa, FL, USA;USF Health Byrd Alzheimer’s Institute, University of South Florida, 33613, Tampa, FL, USA;Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, 33620, Tampa, FL, USA;Research Service, James A Haley Veterans Hospital, 13000 Bruce B Downs Blvd, 33612, Tampa, FL, USA;

关键词: Tau;    FKBP52;    Aha1;    Molecular chaperones;    Alzheimer’s disease;    Neuroinflammation;   

DOI  :  10.1186/s40478-021-01159-w

来源: Springer

【 摘 要 】

The microtubule associated protein tau is an intrinsically disordered phosphoprotein that accumulates under pathological conditions leading to formation of neurofibrillary tangles, a hallmark of Alzheimer’s disease (AD). The mechanisms that initiate the accumulation of phospho-tau aggregates and filamentous deposits are largely unknown. In the past, our work and others’ have shown that molecular chaperones play a crucial role in maintaining protein homeostasis and that imbalance in their levels or activity can drive tau pathogenesis. We have found two co-chaperones of the 90 kDa heat shock protein (Hsp90), FK506-binding protein 52 (FKBP52) and the activator of Hsp90 ATPase homolog 1 (Aha1), promote tau aggregation in vitro and in the brains of tau transgenic mice. Based on this, we hypothesized that increased levels of these chaperones could promote tau misfolding and accumulation in the brains of aged wild-type mice. We tested this hypothesis by overexpressing Aha1, FKBP52, or mCherry (control) proteins in the hippocampus of 9-month-old wild-type mice. After 7 months of expression, mice were evaluated for cognitive and pathological changes. Our results show that FKBP52 overexpression impaired spatial reversal learning, while Aha1 overexpression impaired associative learning in aged wild-type mice. FKBP52 and Aha1 overexpression promoted phosphorylation of distinct AD-relevant tau species. Furthermore, FKBP52 activated gliosis and promoted neuronal loss leading to a reduction in hippocampal volume. Glial activation and phospho-tau accumulation were also detected in areas adjacent to the hippocampus, including the entorhinal cortex, suggesting that after initiation these pathologies can propagate through other brain regions. Overall, our findings suggest a role for chaperone imbalance in the initiation of tau accumulation in the aging brain.

【 授权许可】

CC BY