标题：β-Amyloid precursor protein transgenic mice that harbor diffuse Aβ deposits but do not form plaques show increased ischemic vulnerability: Role of inflammation
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2002
卷号：99
期号：3
页码：1610-1615
DOI：10.1073/pnas.032670899
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：{beta}-amyloid (A{beta}), derived form the {beta}-amyloid precursor protein (APP), is important for the pathogenesis of Alzheimer's disease (AD), which is characterized by progressive decline of cognitive functions, formation of A{beta} plaques and neurofibrillary tangles, and loss of neurons. However, introducing a human wild-type or mutant APP gene to rodent models of AD does not result in clear neurodegeneration, suggesting that contributory factors lowering the threshold of neuronal death may be present in AD. Because brain ischemia has recently been recognized to contribute to the pathogenesis of AD, we studied the effect of focal brain ischemia in 8- and 20-month-old mice overexpressing the 751-amino acid isoform of human APP. We found that APP751 mice have higher activity of p38 mitogen-activated protein kinase (p38 MAPK) in microglia, the main immune effector cells within the brain, and increased vulnerability to brain ischemia when compared with age-matched wild-type mice. These characteristics are associated with enhanced microglial activation and inflammation but not with altered regulation of cerebral blood flow, as assessed by MRI and laser Doppler flowmetry. Suppression of inflammation with aspirin or inhibition of p38 MAPK with a selective inhibitor, SD-282, abolishes the increased neuronal vulnerability in APP751 transgenic mice. SD-282 also suppresses the expression of inducible nitric-oxide synthase and the binding activity of activator protein 1. These findings elucidate molecular mechanisms of neuronal injury in AD and suggest that antiinflammatory compounds preventing activation of p38 MAPK in microglia may reduce neuronal vulnerability in AD.
