Microglial Phagocytosis of Fibrillar β-Amyloid through a β₁Integrin-Dependent Mechanism

Abstract

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 Fc␥RIII) or complement receptors. Microglia interact with fA␤ through a recently characterized A␤ cell surface receptor complex comprising the B-class scavenger receptor CD36, ␣ 6 ␤ 1 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.

Attenuation of neuroinflammation and Alzheimer's disease pathology by liver x receptors

“…Microglia normally act to clear fA␤ through phagocytosis of amyloid fibrils and large A␤ aggregates (43). Exposure of microglia to fA␤ induces a distinct form of phagocytosis mediated by a ␤1-integrin-dependent process (58), and this process is suppressed in the presence of inflammatory cytokines (22). In our study, LXR agonist treatment resulted in the restoration of fA␤-stimulated phagocytosis, most likely through inhibition of NF B activity (5).…”

Behavior of in vitro cultured ameboid microglial cells migrating on Müller cell end‐feet in the quail embryo retina

“…In these assays, different materials to be phagocytosed, such as latex beads (Dijkstra et al, 2001;Giulian and Baker, 1986), erythrocytes (Stangel and Compston, 2001), zymosan Ohsawa et al, 2000), bacteria (Giulian and Baker, 1986), myelin (Dijkstra et al, 2001;Smith et al, 1998), b-amyloid (Koenigsknecht andLandreth, 2004), and apoptotic cells (Chan et al, 2001;Magnus et al, 2002) were added to the culture system to test the phagocytic ability of microglial cells. In our culture system, phagocytosed MCEF are inherent materials, therefore phagocytosis by microglial cells can be demonstrated without the addition of other materials.…”

“…In fact, Koenigsknecht and Landreth (2004) reported the presence in microglial cells of a b1 integrin-mediated mechanism of phagocytosis in addition to the classical mechanism involving Fc immunoglobulin receptors. Furthermore, Hailer et al (1997) suggested that some molecules in the substrate incorporated by phagocytosis would induce second-messenger pathways that lead to the expression of adhesion molecules.…”

The human-specificCASP4gene product contributes to Alzheimer-related synaptic and behavioural deficits

“…Despite this increased microglial recruitment to plaques, we did not observe significant clearance of either soluble Ab or plaques. In human AD brains, microglia apparently do not effectively clear amyloid plaques (21), and cultured microglia do not efficiently degrade phagocytosed Ab fibrils (57)(58)(59). In addition, amyloid associated microglia have been shown to be primarily derived from peripheral monocytes and may aggravate AD-like phenotypes (23,60).…”

“…Microglia comprise 5-10% of all cells in the brain (14), and carry out innate immune functions, such as phagocytosis of debris from cells and synapses (15) and secretion of factors that can either promote tissue protection and repair or act as neurotoxic agents, depending on the context (16). Mouse microglial cells are recruited to Ab plaques (17), where they are believed to uptake plaques by phagocytosis (18,19) and release inflammatory cytokines (20), however it has been suggested that human microglia do not appear to significantly influence plaque clearance in AD brains (21). In addition to resident microglia, peripheral monocytes infiltrate the brain parenchyma under pathological condition, and several studies have indicated that infiltrating monocytes have distinct functional characteristics compared to resident microglia (22)(23)(24).…”