β-amyloid precursor protein transgenic mice that harbor diffuse Aβ deposits but do not form plaques show increased ischemic vulnerability:: Role of inflammation
β-amyloid precursor protein transgenic mice that harbor diffuse Aβ deposits but do not form plaques show increased ischemic vulnerability:: Role of inflammation
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DOI：
10.1073/pnas.032670899
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发表时间：
2002-02-05
影响因子：
11.1
通讯作者：
Koistinaho, J
中科院分区：
文献类型：
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作者：
Koistinaho, M;Kettunen, MI;Koistinaho, J
β-淀粉样蛋白（AP）是由G-淀粉样前体蛋白（APP）衍生而来的，在阿尔茨海默病（AD）的发病机制中起重要作用，AD的特征是认知功能进行性下降、AP斑块和神经元缠结的形成以及神经元的丢失。然而，将人野生型或突变型APP基因引入AD啮齿动物模型不会导致明显的神经变性，这表明AD中可能存在降低神经元死亡阈值的促成因素。由于脑缺血最近被认为有助于AD的发病机制，我们研究了局灶性脑缺血在8个月和20个月大的小鼠中的作用，这些小鼠过表达人APP的751个氨基酸同种型，我们发现APP 751小鼠具有更高的p38丝裂原活化蛋白激酶活性（p38 MAPK）在小胶质细胞，脑内的主要免疫效应细胞，并增加脆弱性脑缺血相比，年龄匹配的野生型小鼠。这些特征与增强的小胶质细胞活化和炎症有关，但与脑血流调节的改变无关，如MRI和激光多普勒血流仪所评估的。用阿司匹林抑制炎症或用选择性抑制剂SD-282抑制p38 MAPK可消除APP 751转基因小鼠中增加的神经元脆弱性。SD-282还抑制诱导型一氧化氮合酶的表达和激活蛋白1的结合活性。这些发现阐明了AD中神经元损伤的分子机制，并表明阻止小胶质细胞中p38 MAPK活化的化合物可降低AD中神经元的脆弱性。
beta-amyloid (AP), derived form the G-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 AP 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.