Functional Gene Trap Mutagenesis Screen for Genes and Molecular Mechanisms Underlying Amyloid-β-induced Inflammasome-mediated Neuronal Death

Abstract Background Neuroinflammation is increasingly recognized for its roles in AD pathogenesis which, in part, links amyloid-beta (Aβ) to neuronal death. While commonly associated with glial cells, neurons themselves are able to participate in neuroinflammation signalling, potentially leading to widespread neuronal suicide. The presence of the inflammasomes such as NLRP1 in neurons accelerates Aβ-induced neuroinflammation and has been shown to trigger neuronal pyroptosis in murine AD models. However, the pathways involved in Aβ activation of inflammasomes has yet to be elucidated, especially in humans. In this study, we utilized a gene trap mutagenesis phenotypic screen approach to uncover the genes and biological pathways involved in inflammasome signalling in neurons and how it contributed to Aβ-induced neuronal death. Results Aβ significantly accelerated neuroinflammatory cell death in the presence of primed inflammasome. The gene trap mutagenesis screen discovered genes related to mitochondria function and TGF-β signalling as significant contributors to Aβ-induced inflammasome-driven neuronal death. Additionally, genes associated with cytoskeletal reorganization were found to confer neuroprotection. Conclusion Our data presents a list of potentially important components of inflammasome signalling in neurons which makes promising therapeutic targets for future drug development against neuroinflammation in AD.