dipeptides activate the NLRP3 inflammasome.

Brain Commun

Division of Neuroscience, Faculty of Biology, Medicine and Health, School of Biological Sciences, University of Manchester, Manchester M13 9PL, UK.

Published: August 2024

AI Article Synopsis

  • * Neuroinflammation is prevalent in both conditions, and a specific inflammasome complex is identified as a driver of this damaging inflammation, similar to other neurodegenerative diseases like Alzheimer's.
  • * Research shows that the toxic dipeptide, poly-glycine-arginine, activates the inflammasome in immune cells, leading to inflammation, but several existing anti-inflammatory drugs can mitigate this activation, suggesting potential new treatments.

Article Abstract

Frontotemporal dementia and amyotrophic lateral sclerosis are neurodegenerative diseases with considerable clinical, genetic and pathological overlap. The most common cause of both diseases is a hexanucleotide repeat expansion in . The expansion is translated to produce five toxic dipeptides, which aggregate in patient brain. Neuroinflammation is a feature of frontotemporal dementia and amyotrophic lateral sclerosis; however, its causes are unknown. The nod-like receptor family, pyrin domain-containing 3 inflammasome is implicated in several other neurodegenerative diseases as a driver of damaging inflammation. The inflammasome is a multi-protein complex which forms in immune cells in response to tissue damage, pathogens or aggregating proteins. Inflammasome activation is observed in models of other neurodegenerative diseases such as Alzheimer's disease, and inflammasome inhibition rescues cognitive decline in rodent models of Alzheimer's disease. Here, we show that a dipeptide arising from the expansion, poly-glycine-arginine, activated the inflammasome in microglia and macrophages, leading to secretion of the pro-inflammatory cytokine, interleukin-1β. Poly-glycine-arginine also activated the inflammasome in organotypic hippocampal slice cultures, and immunofluorescence imaging demonstrated formation of inflammasome specks in response to poly-glycine-arginine. Several clinically available anti-inflammatory drugs rescued poly-glycine-arginine-induced inflammasome activation. These data suggest that dipeptides contribute to the neuroinflammation observed in patients, and highlight the inflammasome as a potential therapeutic target for frontotemporal dementia and amyotrophic lateral sclerosis.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11369816PMC
http://dx.doi.org/10.1093/braincomms/fcae282DOI Listing

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