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

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...

Full description

Saved in:

Bibliographic Details
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
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 The authors declare no competing or financial interests. Handling Editor: Steven Clapcote Competing interests
ISSN:	1754-8403 1754-8411 1754-8411
DOI:	10.1242/dmm.050635