MEGF10 knockout promotes cortical and hippocampal amyloid deposition in AD mouse model

Abstract

Multiple epidermal growth factor (EGF)-like domains 10 (MEGF10) is a single-pass transmembrane protein expressed in neurons and astrocytes, functioning as a phagocytic receptor for apoptotic cells and mediating homotypic adhesion in the mammalian brain. We previously demonstrated that MEGF10 facilitates the uptake of toxic amyloid-β (Aβ) species Aβ42 and Aβ43 by neurons and astrocytes in vitro. However, whether MEGF10 also serves as a phagocytic receptor for Aβ in the brain in vivo, particularly under neurodegenerative conditions such as Alzheimer’s disease (AD), remains unclear. To address this question, we generated MEGF10 knockout mice on an AD model background and analyzed brain Aβ deposition and Aβ42 levels. We observed a significant increase in Aβ deposition and Aβ42 levels in the hippocampus and cortex of MEGF10-deficient AD mice compared with AD model controls. To assess cognitive function, we performed the Y-maze test. MEGF10 knockout AD mice exhibited impaired spatial memory relative to wild-type controls; however, no significant difference was found between MEGF10 knockout AD mice and AD model controls. These findings suggest that MEGF10 contributes to Aβ clearance in the brain and support its role as a phagocytic receptor for Aβ in vivo, potentially helping to maintain brain homeostasis in the context of Alzheimer’s pathology.