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Cell-based Assay to Study Antibody-mediated Tau Clearance by Microglia
Published on: November 9, 2018
Microglial phagocytosis of fibrillar beta-amyloid through a beta1 integrin-dependent mechanism
Jessica Koenigsknecht1, Gary Landreth
1Alzheimer Research Laboratory, Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
Abstract:
Microglia are the principle immune effector and phagocytic cells in the CNS. These cells are associated with fibrillar beta-amyloid (fAbeta)-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 Abeta deposits but can efficiently phagocytose Abeta fibrils and plaques in vitro. We report that exposure of microglia to fAbeta in vitro induces phagocytosis through mechanisms distinct from those used by the classical phagocytic receptors, the Ig receptors (FcRgammaI and FcgammaRIII) or complement receptors. Microglia interact with fAbeta through a recently characterized Abeta cell surface receptor complex comprising the B-class scavenger receptor CD36, alpha6beta1 integrin, and CD47 (integrin-associated protein). Antagonists specific for each component of the receptor complex blocks fAbeta-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 beta(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 fAbeta through a receptor-mediated, nonclassical phagocytic mechanism.
Insights
Microglia in Alzheimer's disease (AD) fail to clear amyloid-beta (Abeta) plaques in the brain. This study identifies a novel receptor complex on microglia that mediates Abeta phagocytosis via a nonclassical pathway.
Area of Science:
- Neuroimmunology
- Cellular Biology
- Alzheimer's Disease Research
Background:
- Microglia are the primary immune cells in the central nervous system (CNS), acting as effector and phagocytic cells.
- In Alzheimer's disease (AD), microglia associate with fibrillar beta-amyloid (fAbeta) plaques, becoming activated and contributing to neuroinflammation.
- Paradoxically, AD microglia fail to phagocytose Abeta in vivo, despite efficient in vitro clearance.
Purpose of the Study:
- To investigate the mechanisms by which microglia phagocytose fibrillar beta-amyloid (fAbeta) in vitro.
- To identify the specific cell surface receptors involved in fAbeta uptake by microglia.
- To characterize the phagocytic pathway utilized by microglia for Abeta clearance.
Main Methods:
- In vitro exposure of microglia to fibrillar beta-amyloid (fAbeta).
- Utilized specific receptor antagonists to block fAbeta-stimulated phagocytosis.
- Investigated phagocytosis mechanisms distinct from classical phagocytic receptors (FcRgammaI, FcgammaRIII, complement receptors).
Main Results:
- Microglia phagocytose fAbeta via mechanisms distinct from classical phagocytic receptors.
- A novel Abeta cell surface receptor complex involving CD36, alpha6beta1 integrin, and CD47 mediates fAbeta uptake.
- Blocking components of this receptor complex inhibits fAbeta-stimulated phagocytosis.
- Phagocytosis is driven by a beta(1) integrin-linked process, distinct from classical phagocytic mechanisms.
Conclusions:
- Microglia utilize a novel, receptor-mediated, nonclassical phagocytic mechanism to internalize fAbeta.
- The identified receptor complex (CD36, alpha6beta1 integrin, CD47) is crucial for this nonclassical phagocytosis.
- Understanding this pathway may offer new therapeutic targets for enhancing Abeta clearance in Alzheimer's disease.
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