Sci. STKE, 10 December 2002
Alzheimer's Disease Inflammatory Pathways in Alzheimer's Disease
Two groups have investigated the role of cell surface proteins in microglial activation and the inflammatory effects of β-amyloid (Aβ), research that could have implications for therapy to treat Alzheimer's disease. Alzheimer's disease, the most common neurodegenerative disorder, is characterized by aggregates of fibrillar Aβ derived from misprocessing of amyloid precursor protein (APP). Aβ deposits are surrounded by activated microglia and astrocytes, which have been postulated to contribute to Alzheimer's pathophysiology by establishing a chronic inflammatory state. Moore et al. used Western analysis in wild-type and CD36 knockout mice to implicate the scavenger receptor CD36, which mediates Aβ binding to cells of macrophage lineage, in a cascade involving tyrosine phosphorylation of several macrophage proteins, including mitogen-activated protein kinases ERK1 and ERK2 (ERK1/2 MAPK), in response to Aβ. Immunostaining confirmed that Aβ-triggered phosphorylation of ERK1 and ERK2 in microglia also involved CD36. The authors used pharmacological analysis, together with various knockout mice, to implicate Src family kinases in ERK1 and ERK2 activation and macrophage inflammatory responses to Aβ in vitro and microglial recruitment in vivo. Tan et al. used a CD40 ligand (CD40L) knockout to implicate CD40L, an immunoregulatory molecule, in the microgliosis, astrocytosis, and Aβ plaque formation seen in a transgenic mouse model of Alzheimer's disease. The authors further showed that depletion of CD40L by injection of an antibody against CD40L decreased amyloidogenic processing of APP and inhibited plaque formation in vivo, whereas in neuroblastoma cells that overexpressed APP, CD40L increased amyloidogenic APP processing. Both lines of research could ultimately lead to novel therapies for Alzheimer's disease.
K. J. Moore, J. El Khoury, L. A. Medeiros, K. Terada, C. Geula, A. D. Luster, M. W. Freeman, A CD36-initiated signaling cascade mediates inflammatory effects of β-amyloid. J. Biol. Chem. 277, 47373-47379 (2002). [Abstract] [Full Text]
J. Tan, T. Town, F. Crawford, T. Mori, A. DelleDonne, R. Crescenti, D. Obregon, R. A. Flavell, M. J. Mullan, Role of CD40 ligand in amyloidosis in transgenic Alzheimer's mice. Nat. Neurosci. 5, 1288-1293 (2002). [Online Journal]
Citation: Inflammatory Pathways in Alzheimer's Disease. Sci. STKE 2002, tw461 (2002).
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