Geranylgeranylacetone Ameliorates Beta-Amyloid Toxicity and Extends Lifespan via the Heat Shock Response in Caenorhabditis elegans

• Published in: Frontiers in aging 2022-04, Vol.3, p.846977
• Main Authors: Mossiah, Isiah, Perez, Sabrina M, Stanley, Taylor R, Foley, Michaela K, Kim Guisbert, Karen S, Guisbert, Eric
• Format: Article
• Language: English
• Subjects: Aging; Alzheimer’s disease; geranylgeranylacetone; heat shock response; HSF1; longevity
• ISSN: 2673-6217; 2673-6217
• DOI: 10.3389/fragi.2022.846977

Activation of a cytoprotective cellular pathway known as the heat shock response (HSR) is a promising strategy for the treatment of Alzheimer's disease and other neurodegenerative diseases. Geranylgeranylacetone (GGA) is a commonly used anti-ulcer drug in Japan that has been shown to activate the HSR. Here, we establish as a model system to investigate the effects of GGA. First, we show that GGA-mediated activation of the HSR is conserved in worms. Then, we show that GGA can ameliorate beta-amyloid toxicity in both muscle and neuronal worm Alzheimer's disease models. Finally, we find that exposure to GGA is sufficient to extend the lifespan of wild-type worms. Significantly, the beneficial effects of GGA on both beta-amyloid toxicity and lifespan are dependent on HSR activation. Taken together, this research supports further development of GGA as a therapeutic for Alzheimer's disease, provides evidence that HSR activation is a relevant therapeutic mechanism, and indicates that the beneficial effects of GGA are not limited to disease.