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The Journal of Neuroscience, April 1, 2003, 23(7):2665
A Cell Surface Receptor Complex for Fibrillar  -Amyloid
Mediates Microglial Activation
Maria E.
Bamberger1, 2,
Meera E.
Harris2,
Douglas
R.
McDonald3,
Jens
Husemann4, and
Gary E.
Landreth2
Alzheimer Research Laboratory, 1 Program in Cell
Biology and 2 Departments of Neurosciences and Neurology,
Case Western Reserve University School of Medicine, Cleveland, Ohio
44106, 3 Department of Immunology, Children's Hospital,
Boston, Massachusetts 02115, and 4 Department of Physiology
and Cellular Biophysics, Columbia University College of Physicians and
Surgeons, New York, New York 10032
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  -amyloid
(A) 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 A
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  61-integrin.
Antagonists of scavenger receptors, CD36, CD47, and
61 inhibited the adhesion of THP-1 monocytes to A fibrils. In addition, peptide competitors of A fibril interactions with CD36, scavenger receptors, CD47, and the
61-integrin inhibited A stimulation of
Tyr kinase-based signaling cascades in both THP-1 monocytes and murine
microglia as well as interleukin 1 production. A scavenger receptor
antagonist and antibodies specific for CD36 and the
1-integrin subunit also inhibited the A-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 A
fibrils and mediate their activation of intracellular signaling
cascades represents a potential intervention point in the treatment of
Alzheimer's disease.
Key words:
Alzheimer's disease; -amyloid; 61-integrin; CD36; CD47; microglia; THP-1
monocytes; scavenger receptor; signal transduction; receptors; Tyr
kinase
Copyright © 2003 Society for Neuroscience 0270-6474/03/2372665-10$05.00/0
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