Hsp90 co-chaperones, FKBP52 and Aha1, promote tau pathogenesis in aged wild-type mice.
Hsp90 co-chaperones, FKBP52 and Aha1, promote tau pathogenesis in aged wild-type mice.
复制标题
DOI：
10.1186/s40478-021-01159-w
复制
发表时间：
2021-04-08
影响因子：
7.1
通讯作者：
Blair LJ
中科院分区：
文献类型：
--
作者：
Criado-Marrero M;Gebru NT;Blazier DM;Gould LA;Baker JD;Beaulieu-Abdelahad D;Blair LJ
微管相关蛋白tau是一种内在紊乱的磷蛋白，在病理条件下积累导致神经原纤维缠结的形成，这是阿尔茨海默病（AD）的标志。启动磷-tau聚集体和丝状沉积物积累的机制在很大程度上是未知的。过去，我们和其他人的工作已经表明，分子伴侣在维持蛋白质稳态中起着至关重要的作用，其水平或活动的不平衡可以驱动tau发病机制。我们发现90kda热休克蛋白（Hsp90）的两个共同伴侣，fk506结合蛋白52 （FKBP52）和Hsp90 atp酶同源物激活因子1 (Aha1)，在体外和tau转基因小鼠的大脑中促进tau聚集。基于此，我们假设这些伴侣蛋白水平的增加可以促进老年野生型小鼠大脑中tau蛋白的错误折叠和积累。我们通过在9月龄野生型小鼠的海马体中过表达Aha1、FKBP52或mCherry（对照）蛋白来验证这一假设。表达7个月后，评估小鼠的认知和病理变化。结果表明，老年野生型小鼠FKBP52过表达会损害空间反转学习，而Aha1过表达会损害联想学习。FKBP52和Aha1的过表达促进了ad相关tau蛋白的磷酸化。此外，FKBP52激活胶质瘤，促进神经元丢失，导致海马体积减少。在海马附近的区域，包括内嗅皮层，也检测到胶质细胞激活和磷酸化tau蛋白积累，这表明在开始后，这些病变可以通过其他大脑区域传播。总的来说，我们的研究结果表明，在老化的大脑中，伴侣蛋白失衡在tau积累的启动中起着重要作用。在线版本包含补充材料，可在10.1186/s40478-021-01159-w获得。
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. The online version contains supplementary material available at 10.1186/s40478-021-01159-w.
登录
查看更多内容
影响因子：
4.8
作者：
Erlejman, Alejandra G.;De Leo, Sonia A.;Galigniana, Mario D.
通讯作者：
Galigniana, Mario D.
影响因子：
12.4
作者：
Duque, Sandra;Joussemet, Beatrice;Barkats, Martine
通讯作者：
Barkats, Martine
影响因子：
4.3
作者：
DeVos SL;Corjuc BT;Oakley DH;Nobuhara CK;Bannon RN;Chase A;Commins C;Gonzalez JA;Dooley PM;Frosch MP;Hyman BT
通讯作者：
Hyman BT
影响因子：
7.1
作者：
Domínguez-Álvaro M;Montero-Crespo M;Blazquez-Llorca L;Insausti R;DeFelipe J;Alonso-Nanclares L
通讯作者：
Alonso-Nanclares L
影响因子：
8.8
作者：
Brehme M;Voisine C;Rolland T;Wachi S;Soper JH;Zhu Y;Orton K;Villella A;Garza D;Vidal M;Ge H;Morimoto RI
通讯作者：
Morimoto RI