Activation of the heat shock response as a therapeutic strategy for tau toxicity

• Published in: Disease models & mechanisms Vol. 17; no. 9
• Main Authors: Stanley, Taylor R, Otero, Elizabeth M, Knight, Amy L, Saxton, Aleen D, Ding, Xinxing, Borgen, Melissa, Kraemer, Brian C, Kim Guisbert, Karen S, Guisbert, Eric
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Ltd 01.09.2024; The Company of Biologists
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; alzheimer’s disease; Amyloid beta-Peptides - metabolism; Amyloid beta-Peptides - toxicity; Animals; Animals, Genetically Modified; caenorhabditis elegans; Caenorhabditis elegans - drug effects; Caenorhabditis elegans - metabolism; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; Diterpenes - pharmacology; heat shock response; Heat-Shock Response - drug effects; hsf1; Humans; Longevity - drug effects; tau (mapt); tau Proteins - metabolism; Transcription Factors; Heat shock response; Caenorhabditis elegans; Alzheimer’s disease; Tau (MAPT); HSF1
• ISSN: 1754-8403; 1754-8411; 1754-8411
• DOI: 10.1242/dmm.050635

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.