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The Journal of Neuroscience, November 3, 2004, 24(44):9838-9846; doi:10.1523/JNEUROSCI.2557-04.2004
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Neurobiology of Disease
Microglial Phagocytosis of Fibrillar  -Amyloid through a 1 Integrin-Dependent Mechanism
Jessica Koenigsknecht and
Gary Landreth
Alzheimer Research Laboratory, Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106
Microglia are the principle immune effector and phagocytic cells in the CNS. These cells are associated with fibrillar  -amyloid (fA)-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 A deposits but can efficiently phagocytose A fibrils and plaques in vitro.
We report that exposure of microglia to fA in vitro induces phagocytosis through mechanisms distinct from those used by the classical phagocytic receptors, the Ig receptors (FcR I and FcRIII) or complement receptors. Microglia interact with fA through a recently characterized A cell surface receptor complex comprising the B-class scavenger receptor CD36,  61 integrin, and CD47 (integrin-associated protein). Antagonists specific for each component of the receptor complex blocks fA-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 1 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 fA through a receptor-mediated, nonclassical phagocytic mechanism.
Key words: phagocytosis; -amyloid; Alzheimer's disease; microglia; 61-integrin; CD36
Received June 28, 2004;
revised September 16, 2004;
accepted September 16, 2004.
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