A cell surface receptor complex for fibrillar beta-amyloid mediates microglial activation.
Senile plaques found in the Alzheimer's disease brain are foci of local inflammatory reactions mediated by plaque-associated microglia. The interaction of microglia with compacted deposits of beta-amyloid (Abeta) fibrils results in the stimulation of intracellular Tyr kinase-based signaling cascades and cellular activation, leading to the secretion of proinflammatory molecules. This study identifies a cell surface receptor complex that mediates the binding of microglia to Abeta fibrils and the subsequent activation of intracellular signaling pathways leading to a proinflammatory response. The receptor complex includes the B-class scavenger receptor CD36, the integrin-associated protein/CD47, and the alpha(6)beta(1)-integrin. Antagonists of scavenger receptors, CD36, CD47, and alpha(6)beta(1) inhibited the adhesion of THP-1 monocytes to Abeta fibrils. In addition, peptide competitors of Abeta fibril interactions with CD36, scavenger receptors, CD47, and the alpha(6)beta(1)-integrin inhibited Abeta stimulation of Tyr kinase-based signaling cascades in both THP-1 monocytes and murine microglia as well as interleukin 1beta production. A scavenger receptor antagonist and antibodies specific for CD36 and the beta(1)-integrin subunit also inhibited the Abeta-stimulated generation of reactive oxygen species. Importantly, the principal components of this receptor complex are shared with those for other fibrillar proteins and thus represent general elements through which myeloid lineage cells recognize complex fibrillar proteins. Identification of the cell surface molecules that interact with Abeta fibrils and mediate their activation of intracellular signaling cascades represents a potential intervention point in the treatment of Alzheimer's disease.
Bamberger
Maria E
ME
Alzheimer Research Laboratory, Program in Cell Biology and Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
Harris
Meera E
ME
McDonald
Douglas R
DR
Husemann
Jens
J
Landreth
Gary E
GE
D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D015703:Antigens, CD / Q000502:physiology; D018955:CD36 Antigens / Q000502:physiology; D051928:CD47 Antigen; D002352:Carrier Proteins / Q000502:physiology; D002448:Cell Adhesion; D002460:Cell Line; D002478:Cells, Cultured; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology; D006801:Humans; D039121:Integrin alpha6beta1 / Q000502:physiology; D046911:Macromolecular Substances; D008565:Membrane Proteins; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D008954:Models, Biological; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D010446:Peptide Fragments / Q000494:pharmacology; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000032:analysis; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000737:chemistry / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011956:Receptors, Cell Surface / Q000502:physiology*; D011971:Receptors, Immunologic / Q000502:physiology; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B; D015398:Signal Transduction
D016229:Amyloid beta-Peptides; D015703:Antigens, CD; D018955:CD36 Antigens; D051928:CD47 Antigen; C497894:CD47 protein, human; D002352:Carrier Proteins; C497895:Cd47 protein, mouse; D039121:Integrin alpha6beta1; D046911:Macromolecular Substances; D008565:Membrane Proteins; D010446:Peptide Fragments; D011506:Proteins; D000067759:Receptor for Advanced Glycation End Products; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go