Long-term accumulation of amyloid-β, β-secretase, presenilin-1, and caspase-3 in damaged axons following brain trauma
Long-term accumulation of amyloid-β, β-secretase, presenilin-1, and caspase-3 in damaged axons following brain trauma
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DOI：
10.1016/s0002-9440(10)63303-2
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发表时间：
2004-08-01
影响因子：
6
通讯作者：
Smith, DH
中科院分区：
文献类型：
--
作者：
Chen, XH;Siman, R;Smith, DH
在人类脑创伤后的几天内发现了由淀粉样蛋白β（Abeta）组成的斑块，类似于阿尔茨海默病（AD）的标志性斑块病理学。在这里，我们评估了这种Abeta的潜在来源和可能导致其产生的长期机制。在猪脑中，通过在冠状面内旋转头部110 °超过20 ms的加速度来诱导惯性性脑损伤。在损伤后3小时、3天、7天和6个月对动物实施安乐死。使用淀粉样前体蛋白（APP）、Abeta肽、β位点APP裂解酶（BACE）、早老素-1（PS-1）、半胱天冬酶-3和半胱天冬酶介导的APP裂解（CCA）特异性抗体对脑进行免疫组织化学和Western印迹分析。在损伤后6个月的所有时间点，在肿胀的轴突中发现所有这些因子的大量共积累。对受损大脑的蛋白质印迹分析证实了这些因子的蛋白质水平大幅增加，特别是在白色物质中。这些数据表明，受损的轴突运输由于创伤诱导APP与BACE，PS-1，和活化的半胱天冬酶的长期病理性共积累。这些因子的异常浓度可能导致APP蛋白水解和Abeta在轴突膜隔室内形成。
Plaques composed of amyloid beta(Abeta) have been found within days following brain trauma in humans, similar to the hallmark plaque pathology of Alzheimer's disease (AD). Here, we evaluated the potential source of this Abeta and long-term mechanisms that could lead to its production. Inertial brain injury was induced in pigs via head rotational acceleration of 110degrees over 20 ms in the coronal plane. Animals were euthanized at 3 hours, 3 days, 7 days, and 6 months post-injury. Immunohistochemistry and Western blot analyses of the brains were performed using antibodies specific for amyloid precursor protein (APP), Abeta peptides, beta-site APP-cleaving enzyme (BACE), presenilin-1 (PS-1), caspase-3, and caspase-mediated cleavage of APP (CCA). Substantial co-accumulation for all of these factors was found in swollen axons at all time points up to 6 months following injury. Western blot analysis of injured brains confirmed a substantial increase in the protein levels of these factors, particularly in the white matter. These data suggest that impaired axonal transport due to trauma induces long-term pathological co-accumulation of APP with BACE, PS-1, and activated caspase. The abnormal concentration of these factors may lead to APP proteolysis and Abeta formation within the axonal membrane compartment.