Cerebral amyloid angiopathy is a pathogenic lesion in Alzheimer's disease due to a novel presenilin 1 mutation
Cerebral amyloid angiopathy is a pathogenic lesion in Alzheimer's disease due to a novel presenilin 1 mutation
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DOI：
10.1093/brain/124.12.2383
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发表时间：
2001-12-01
期刊：
影响因子：
14.5
通讯作者：
Van Broeckhoven, C
中科院分区：
文献类型：
--
作者：
Dermaut, B;Kumar-Singh, S;Van Broeckhoven, C
致密核斑块被认为是阿尔茨海默病大脑中淀粉样蛋白沉积的致病性类型，因为它们主要与营养不良的神经突相关。然而，在bbbb90的阿尔茨海默病病例中，淀粉样蛋白也沉积在脑血管壁上（嗜血性淀粉样血管病；CAA），但其在阿尔茨海默病发病机制中的作用仍是谜。在这里，我们报告了一个家族（家族GB），其中早发性阿尔茨海默病是由一种新的早老素1突变（L282V）引起的。这是一种异常严重的CAA，让人想起我们之前报道的弗拉芒淀粉样蛋白前体蛋白（A692G）突变，这种突变会导致阿尔茨海默病和/或脑出血。然而，在GB家族中，该疾病表现为典型的进行性阿尔茨海默病，没有中风或卒中样发作。同样，神经影像学研究和神经病理学检查倾向于退行性痴呆而不是血管性痴呆。有趣的是，一项免疫组织化学研究显示，与引起致密核淀粉样斑块类似，CAA似乎也能够引发强烈的局部营养不良和炎症反应。观察到的神经元丢失、tau和泛素阳性神经突的存在、微胶质细胞和星形胶质细胞增生以及补体活化都表明了这一点。综上所述，这些数据表明，与致密核神经斑块一样，CAA可能是一种致病性病变，对阿尔茨海默病中发生的进行性神经退行性变有重要影响。
The dense-cored plaques are considered the pathogenic type of amyloid deposition in Alzheimer's disease brains because of their predominant association with dystrophic neurites. Nevertheless, in >90% of cases of Alzheimer's disease amyloid is also deposited in cerebral blood vessel walls (congophilic amyloid angiopathy; CAA) but its role in Alzheimer's disease pathogenesis remains enigmatic. Here, we report a family (family GB) in which early-onset Alzheimer's disease was caused by a novel presenilin 1 mutation (L282V). This was unusually severe CAA reminiscent of the Flemish amyloid precursor protein (A692G) mutation we reported previously, which causes Alzheimer's disease and/or cerebral haemorrhages. In family GB, however, the disease presented as typical progressive Alzheimer's disease in the absence of strokes or stroke-like episodes. Similarly, neuroimaging studies and neuropathological examination favoured a degenerative over a vascular dementia. Interestingly, an immunohistochemical study revealed that, similar to causing dense-cored amyloid plaques, CAA also appeared capable of instigating a strong local dystrophic and inflammatory reaction. This was suggested by the observed neuronal loss, the presence of tau- and ubiquitin-positive neurites, micro- and astrogliosis, and complement activation. Together, these data suggest that, like the dense-cored neuritic plaques, CAA might represent a pathogenic lesion that contributes significantly to the progressive neurodegeneration that occurs in Alzheimer's disease.