Genes associated with amyloid-beta-induced inflammasome-mediated neuronal death identified using functional gene trap mutagenesis approach

Yap, Jeremy Kean Yi and Pickard, Benjamin Simon and Gan, Sook Yee and Chan, Elaine Wan Ling (2021) Genes associated with amyloid-beta-induced inflammasome-mediated neuronal death identified using functional gene trap mutagenesis approach. International Journal of Biochemistry and Cell Biology, 136. 106014. ISSN 1357-2725

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    Abstract

    Alzheimer's disease is an irreversible neurodegenerative disease, which accounts for most dementia cases. Neuroinflammation is increasingly recognised for its roles in Alzheimer's disease pathogenesis which, in part, links amyloid-beta to neuronal death. Neuroinflammatory signalling can be exhibited by neurons themselves, potentially leading to widespread neuronal cell death, although neuroinflammation is commonly associated with glial cells. The presence of the inflammasomes such as nucleotide-binding leucine-rich repeat receptors protein 1 in neurons accelerates amyloid-beta -induced neuroinflammation and has been shown to trigger neuronal pyroptosis in murine Alzheimer's disease models. However, the pathways involved in amyloid-beta activation of inflammasomes have yet to be elucidated. In this study, a gene trap mutagenesis approach was utilised to resolve the genes functionally involved in inflammasome signalling within neurons, and the mechanism behind amyloid-beta-induced neuronal death. The results indicate that amyloid-beta significantly accelerated neuroinflammatory cell death in the presence of a primed inflammasome (the NLR family pyrin domain-containing 1). The mutagenesis screen discovered the atypical mitochondrial Ras homolog family member T1 as a significant contributor to amyloid-beta-induced inflammasome -mediated neuronal death. The mutagenesis screen also identified two genes involved in transforming growth factor beta signalling, namely Transforming Growth Factor Beta Receptor 1 and SNW domain containing 1. Additionally, a gene associated with cytoskeletal reorganisation, SLIT-ROBO Rho GTPase Activating Protein 3 was found to be neuroprotective. In conclusion, these genes could play important roles in inflammasome signalling in neurons, which makes them promising therapeutic targets for future drug development against neuroinflammation in Alzheimer's disease.

    ORCID iDs

    Yap, Jeremy Kean Yi, Pickard, Benjamin Simon ORCID logoORCID: https://orcid.org/0000-0002-2374-6329, Gan, Sook Yee and Chan, Elaine Wan Ling;