Neuronal overexpression of mutant amyloid precursor protein results in prominent deposition of cerebrovascular amyloid
Neuronal overexpression of mutant amyloid precursor protein results in prominent deposition of cerebrovascular amyloid
复制标题
DOI：
10.1073/pnas.96.24.14088
复制
发表时间：
1999-11-23
影响因子：
11.1
通讯作者：
Jucker, M
中科院分区：
文献类型：
--
作者：
Calhoun, ME;Burgermeister, P;Jucker, M
过表达突变型人淀粉样前体蛋白（APP）的转基因小鼠表现出阿尔茨海默病病理学的一个标志，即淀粉样斑块的细胞外沉积。在这里，我们描述了淀粉样蛋白β（A β）在老年APP 23小鼠脑血管系统[脑淀粉样血管病（CAA）]中的显著沉积，与人类衰老和阿尔茨海默病中观察到的有惊人的相似之处。淀粉样蛋白沉积优先发生在小动脉和毛细血管中，并且在单个血管内显示出广泛的异质性（从血管壁中的淀粉样蛋白薄环到大斑块状挤出到神经元）。CAA与局部神经元丢失、突触异常、小胶质细胞激活和微出血有关。尽管有几个因素可能导致人类CAA，但转基因APP的神经元起源、脑脊液中高水平的A β以及APP 23小鼠CAA的区域定位表明，转运和引流途径而不是A β的局部产生或血液摄取是脑血管淀粉样蛋白形成的主要机制。APP-空背景的APP 23小鼠产生了相似程度的斑块和CAA，提供了APP/A β的神经元来源足以诱导脑血管淀粉样蛋白和相关神经变性的进一步证据。
Transgenic mice that overexpress mutant human amyloid precursor protein (APP) exhibit one hallmark of Alzheimer's disease pathology namely the extracellular deposition of amyloid plaques. Here, we describe significant deposition of amyloid beta (A beta) in the cerebral vasculature [cerebral amyloid angiopathy (CAA)] in aging APP23 mice that had striking similarities to that observed in human aging and Alzheimer's disease. Amyloid deposition occurred preferentially in arterioles and capillaries and within individual Vessels showed a wide heterogeneity (ranging from a thin ring of amyloid in the vessel wall to large plaque-like extrusions into the neuropil). CAA was associated with local neuron loss, synaptic abnormalities, microglial activation, and microhemorrhage. Although several factors may contribute to CAA in humans, the neuronal origin of transgenic APP, high levels of A beta in cerebrospinal fluid, and regional localization of CAA in APP23 mice suggest transport and drainage pathways rather than local production or blood uptake of A beta as a primary mechanism underlying cerebrovascular amyloid formation. APP23 mice on an App-null background developed a similar degree of both plaques and CAA, providing further evidence that a neuronal source of APP/A beta is sufficient to induce cerebrovascular amyloid and associated neurodegeneration.