期刊
NEUROCHEMISTRY INTERNATIONAL
卷 39, 期 5-6, 页码 371-380出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/S0197-0186(01)00044-4
关键词
CD40 signaling; CD40-CD40 ligand interaction; Alzheimer's disease pathogenesis
The interaction between CD40 and its cognate ligand, CD40 ligand, is a primary regulator of the peripheral immune response, including modulation of T lymphocyte activation., B lymphocyte differentiation and antibody secretion, and innate immune cell activation, maturation, and survival. Recently, we and others have identified CD40 expression on a variety of CNS cells, including endothelial cells. smooth muscle cells, astroglia and microglia, and have found that, on many of these cells, CD40 expression is enhanced by pro-inflammatory stimuli. Importantly, the CD40-CD40 ligand interaction on microglia triggers a series of intracellular signaling events that are discussed, beginning with Src-family kinase activation and culminating in microglial activation as evidenced by tumor necrosis factor-a secretion. Based on the involvement of microglial activation and brain inflammation in Alzheimer's disease pathogenesis. we have investigated co-stimulation of microglia, smooth muscle. and endothelial cells with CD40 ligand in the presence of low doses of freshly solubilized amyloid-beta peptides. Data reviewed herein show that CD40 ligand and amyloid-beta act synergistically to promote pro-inflammatory responses by these cells, including secretion of interleukin-1 beta by endothelial cells and tumor necrosis factor-alpha by microglia. As these cytokines have been implicated in neuronal injury, a comprehensive model of pro-inflammatory CD40 ligand and amyloid-beta initiated Alzheimer's disease pathogenesis (mediated by multiple CNS cells) is proposed. (C) 2001 Elsevier Science Ltd. All rights reserved.
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