A CD36-initiated Signaling Cascade Mediates Inflammatory Effects of β-Amyloid

Kathryn J Moore,Joseph El Khoury,Lea A Medeiros,Kinya Terada,Changiz Geula,Andrew D Luster,Mason W Freeman

doi:10.1074/jbc.m208788200

Abstract

beta-Amyloid accumulation is associated with pathologic changes in the brain in Alzheimer's disease and has recently been identified in plaques of another chronic inflammatory disorder, atherosclerosis. The class B scavenger receptor, CD36, mediates binding of fibrillar beta-amyloid to cells of the monocyte/macrophage lineage, including brain macrophages (microglia). In this study, we demonstrate that in microglia and other tissue macrophages, beta-amyloid initiates a CD36-dependent signaling cascade involving the Src kinase family members, Lyn and Fyn, and the mitogen-activated protein kinase, p44/42. Interruption of this signaling cascade, through targeted disruption of Src kinases downstream of CD36, inhibits macrophage inflammatory responses to beta-amyloid, including reactive oxygen and chemokine production, and results in decreased recruitment of microglia to sites of amyloid deposition in vivo. The finding that engagement of CD36 by beta-amyloid initiates a Src kinase-dependent production of inflammatory mediators in cells of the macrophage lineage reveals a novel receptor-mediated pro-inflammatory signaling pathway of potential therapeutic importance.

Highlights

␤-Amyloid accumulation is associated with pathologic changes in the brain in Alzheimer’s disease and has recently been identified in plaques of another chronic inflammatory disorder, atherosclerosis
We have recently reported that the class B scavenger receptor, CD36, is expressed on microglia and vascular endothelial cells in the brains of normal and Alzheimer’s disease patients and can mediate binding to fibrillar ␤-amyloid (3)
We show that ␤-amyloid induces association of CD36 with the Src phosphotyrosine kinase (PTK) Lyn and activates a signaling cascade involving another Src kinase family member, Fyn, and p44/42 mitogen-activated protein kinase (MAPK)

Summary

Introduction

␤-Amyloid accumulation is associated with pathologic changes in the brain in Alzheimer’s disease and has recently been identified in plaques of another chronic inflammatory disorder, atherosclerosis. We demonstrate that in microglia and other tissue macrophages, ␤-amyloid initiates a CD36-dependent signaling cascade involving the Src kinase family members, Lyn and Fyn, and the mitogen-activated protein kinase, p44/42.

Results

Conclusion