Acetate-induced reactive astrocytes enhance uptake of the toxic molecule amyloid-β with upregulation of MEGF10 and MERTK

Abstract

BackgroundAmyloid-beta (A beta) is a major toxic molecule linked to the pathogenesis of Alzheimer's disease (AD). Astrocytes, the major homeostatic non-neuronal cells in the brain, contribute to extracellular A beta clearance through phagocytosis; however, the underlying mechanism has been elusive. Acetate serves as an alternative energy substrate to glucose for reactive astrocytes in AD, yet its role in modulating astrocytic A beta uptake has not been fully explored. This study investigated whether acetate induces astrocyte reactivity and subsequently enhances A beta uptake.MethodsPrimary cortical astrocytes treated with acetate (1, 3, and 5 mM) to assess changes in reactive astrocyte-related gene expression, including GFAP, MAOB, C3, and Serpina3n. Astrocytic uptake of A beta oligomer was evaluated by immunohistochemistry following acetate treatment. To examine the involvement of astrocytic phagocytic pathways, the expression levels of MEGF10 and MERTK were analyzed using quantitative real-time PCR.ResultsAcetate treatment dose-dependently increased the expression of reactive astrocyte markers (GFAP, MAOB, C3, and Serpina3n), indicating enhanced astrocytic reactivity. Acetate at 5 mM significantly promoted astrocytic uptake of A beta. In parallel, acetate treatment led to a dose-dependent upregulation of MEGF10 and MERTK, genes associated with astrocytic phagocytosis.ConclusionThese findings suggest that elevated acetate levels induce reactive astrocyte phenotypes and enhance A beta uptake, potentially through activation of the MEGF10/MERTK-mediated phagocytic pathway. Acetate-dependent modulation of astrocyte function may represent a previously underappreciated mechanism influencing A beta clearance in AD.