Taylor R Stanley, Elizabeth M Otero, Amy L Knight, Aleen D Saxton, Xinxing Ding, Melissa Borgen, Brian C Kraemer, Karen S Kim Guisbert, Eric Guisbert
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引用次数: 0
Abstract
Alzheimer's disease is associated with the misfolding and aggregation of two distinct proteins, beta-amyloid and tau. Previously, it has been shown that activation of the cytoprotective heat shock response (HSR) pathway reduces beta-amyloid toxicity. Here, we show that activation of the HSR is also protective against tau toxicity in a cell-autonomous manner. Overexpression of HSF-1, the master regulator of the HSR, ameliorates the motility defect and increases the lifespan of transgenic C. elegans expressing human tau. By contrast, RNA interference of HSF-1 exacerbates the motility defect and shortens lifespan. Targeting regulators of the HSR also affects tau toxicity. Additionally, two small-molecule activators of the HSR, Geranylgeranylacetone (GGA) and Arimoclomol (AC), have substantial beneficial effects. Taken together, this research expands the therapeutic potential of HSR manipulation to tauopathies and reveals that the HSR can impact both beta-amyloid and tau proteotoxicity in Alzheimer's disease.
阿尔茨海默病与两种不同的蛋白质(β-淀粉样蛋白和 tau)的错误折叠和聚集有关。以前的研究表明,激活细胞保护性热休克反应(HSR)途径可降低β-淀粉样蛋白的毒性。在这里,我们发现激活 HSR 还能以细胞自主的方式保护 tau 的毒性。过量表达 HSF-1(HSR 的主调节因子)可改善表达人 tau 的转基因 elegans 的运动缺陷并延长其寿命。相反,RNA干扰HSF-1会加剧运动缺陷并缩短寿命。靶向 HSR 的调节因子也会影响 tau 的毒性。此外,HSR的两种小分子激活剂--Geranylgeranylacetone(GGA)和Arimoclomol(AC)--也有很大的益处。总之,这项研究将 HSR 操作的治疗潜力扩展到了 tau 病症,并揭示了 HSR 可以影响阿尔茨海默病中的β-淀粉样蛋白和 tau 蛋白毒性。
期刊介绍:
Disease Models & Mechanisms (DMM) is an online Open Access journal focusing on the use of model systems to better understand, diagnose and treat human disease.