Microglial overexpression of the M-CSF receptor augments phagocytosis of opsonized Aβ

The role of microglia in Alzheimer’s disease (AD) has come under intense scrutiny recently because microglia may clear amyloid beta (Aβ) by phagocytosis after immunization of transgenic mice. Increased expression of the macrophage colony-stimulating factor receptor (M-CSFR) is an important feature of microglia in AD and transgenic mouse models for AD. Increased expression of M-CSFR on mouse and human microglia accelerates phagocytosis of aggregated Aβ in part through macrophage scavenger receptors. We now show that Aβ phagocytosis by microglia overexpressing M-CSFR is further enhanced by antibody opsonization of Aβ. M-CSFR overexpression increased microglial phagocytosis of opsonized aggregated Aβ in culture medium, and accelerated ingestion of native Aβ from AD brain sections. M-CSFR overexpression also increased microglial expression of Fcγ receptors, and blocking Fcγ receptors attenuated the enhanced Aβ uptake observed after M-CSFR overexpression and antibody opsonization. Microglia in AD and in AD mouse models with increased expression of M-CSFR are likely to rapidly ingest opsonized Aβ after immunization, making high intracerebral antibody titers unnecessary.