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Browsing by Subject "S209F"

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  • Pasculli, Maria Samuela (2024)
    The S209F variant of the Abelson Interactor family member 3 (ABI3) gene has emerged as a risk factor for late-onset Alzheimer’s Disease (LOAD). The ABI3 protein is functionally related to the WAVE Regulatory Complex (WRC) participating in the control of cytoskeletal processes favoring either filopodia for chemotaxis or pseudopodia for phagocytosis. The S209F coding variant is thought to impair phosphorylation of the ABI3 protein leading to dysfunctional association with WRC. In the brain, the ABI3 gene is mainly expressed by microglia, macrophages representing the resident immune cells of the brain. Despite some research about the variant based on rodent models and reporting sometimes contrasting results, the role of the ABI3 S209F variant in AD remains poorly understood. Here, human-induced pluripotent stem cells (h-iPSCs) reprogrammed from fibroblasts of controls and variant carriers are sequenced to ensure retention of the original phenotype upon reprogramming. H-iPSCs are differentiated into microglia (iPSC-derived microglia, iMGL) following an established protocol. Morphological changes and microglia-specific gene expression partially show that iMGL between days 31 and 38 of differentiation in vitro can be considered mature. To assess the functional properties of microglia, cytokines/chemokines production, cathepsin gene expression, lysosomal activity, and Apolipoprotein E (ApoE) protein levels are measured. It is found that S209F microglia downregulate CCL5/RANTES and upregulate cathepsins B and L (CTSB and CTSL) upon LPS+IFNg stimulation which may lead to motility, migratory and endo-lysosomal dysfunctions. Lysosomal activity is found to positively correlate with CD163, but not with either CTSB or CTSL expression. ApoE protein levels show an upregulation trend in S209F microglia which may indicate modifications in lipid metabolism. Metabolic assessment based on mitochondrial respiration and glycolysis does not show any difference between S209F and control microglia, but ABI3 knock-out (KO) shows glycolysis dysfunctions. Overall, this study offers some hints into the mechanisms that make the ABI3 S209F variant a risk factor for AD pointing at the need to investigate microglia motility and migration focusing on pathologically relevant protein aggregates and their clearance and with particular attention to phagocytosis and endo-lysosomal pathway.