Fluoxetine protects against amyloid-beta toxicity, in part via daf-16 mediated cell signaling pathway, in Caenorhabditis elegans.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and is the most common form of dementia in elderly people. The accumulation of amyloid beta (Abeta) is one of the histopathological hallmarks of AD. Abeta is aggregated to form oligomers which are toxic to neurons and are critical to the onset and progression of AD. In a Caenorhabditis elegans (C. elegans) model of AD, human Abeta is expressed intracellularly in the body wall muscle. The expression and subsequent aggregation of Abeta in the muscle lead to progressive paralysis. Although the mechanism of action is unknown, antidepressants have been used with FDA approved drugs for dementia in AD and have been shown to enhance cognitive function in human and in animal models of AD. We found that the antidepressant fluoxetine, a selective serotonin reuptake inhibitor, significantly delayed Abeta-induced paralysis in the C. elegans model of Abeta toxicity by reducing Abeta oligomers. Our results showed that insulin signaling and DAF-16/FOXO transcription factors were required for fluoxetine-mediated delayed paralysis. We also found that fluoxetine increased thermal stress resistance and extended life span. These findings suggests that fluoxetine may have benefit for the treatment of AD by the reduction of proteotoxicity.
Keowkase
Roongpetch
R
Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD 21201, USA.
Aboukhatwa
Marwa
M
Luo
Yuan
Y
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000502:physiology*; D002478:Cells, Cultured; D005473:Fluoxetine / Q000494:pharmacology*; D051858:Forkhead Transcription Factors; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*
D016229:Amyloid beta-Peptides; D029742:Caenorhabditis elegans Proteins; D051858:Forkhead Transcription Factors; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D014157:Transcription Factors; C075222:amyloid beta-protein (1-42); C108831:daf-16 protein, C elegans; D005473:Fluoxetine