Acetate-induced Reactive Astrocytes Enhance Uptake of the Toxic Molecule Amyloid-Β with Upregulation of MEGF10 and MERTK

Amyloid-β (Aβ) 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 Aβ 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 Aβ uptake has not been fully explored. This study investigated whether acetate induces astrocyte reactivity and subsequently enhances Aβ uptake. Primary 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 Aβ 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. Acetate 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 Aβ. In parallel, acetate treatment led to a dose-dependent upregulation of MEGF10 and MERTK, genes associated with astrocytic phagocytosis. These findings suggest that elevated acetate levels induce reactive astrocyte phenotypes and enhance Aβ uptake, potentially through activation of the MEGF10/MERTK-mediated phagocytic pathway. Acetate-dependent modulation of astrocyte function may represent a previously underappreciated mechanism influencing Aβ clearance in AD.