Microglia are the principle immune effector and phagocytic cells in the CNS. These cells are associated with fibrillar β-amyloid (fAβ)-containing plaques found in the brains of Alzheimer's disease (AD) patients. The plaque-associated microglia undergo a phenotypic conversion into an activated phenotype and are responsible for the development of a focal inflammatory response that exacerbates and accelerates the disease process. Paradoxically, despite the presence of abundant activated microglia in the brain of AD patients, these cells fail to mount a phagocytic response to Aβ deposits but can efficiently phagocytose Aβ fibrils and plaques in vitro.

We report that exposure of microglia to fAβ in vitro induces phagocytosis through mechanisms distinct from those used by the classical phagocytic receptors, the Ig receptors (FcRγI and FcγRIII) or complement receptors. Microglia interact with fAβ through a recently characterized Aβ cell surface receptor complex comprising the B-class scavenger receptor CD36, α₆β₁ integrin, and CD47 (integrin-associated protein). Antagonists specific for each component of the receptor complex blocks fAβ-stimulated phagocytosis. These data demonstrated that engagement of this ensemble of receptors is required for induction of phagocytosis. The phagocytic response stimulated by this receptor complex is driven principally by a β₁ integrin-linked process that is morphologically and mechanistically distinct from the classical type I and type II phagocytic mechanisms. These data provide evidence for phagocytic uptake of fAβ through a receptor-mediated, nonclassical phagocytic mechanism.