The length of amyloid-beta in hereditary cerebral hemorrhage with amyloidosis, Dutch type - Implications for the role of amyloid-beta 1-42 in Alzheimer's disease
The length of amyloid-beta in hereditary cerebral hemorrhage with amyloidosis, Dutch type - Implications for the role of amyloid-beta 1-42 in Alzheimer's disease
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DOI：
10.1074/jbc.271.50.32185
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发表时间：
1996-12-13
影响因子：
4.8
通讯作者：
Frangione, B
中科院分区：
文献类型：
--
作者：
Castano, EM;Prelli, F;Frangione, B
遗传性脑出血伴淀粉样变性，荷兰型（HCEFWA-D），淀粉样蛋白β（A β）的遗传变体（E22 Q）主要积聚在软脑膜和大脑皮层的小血管中，导致在生命的第五或第六十年中的致命性中风。神经系统中的A β沉积主要以类胶质、刚果红阴性沉积物的形式发生，而成熟的神经炎斑块和神经系统缠结，阿尔茨海默病（AD）中的标志性病变特征性地不存在。关于AD的病理发生的最新假设指出，延伸至残基42-43的A β（与较短的种类相反）可以播种淀粉样蛋白形成并引发AD中神经炎斑的发展，随后是神经元损伤。我们对3例HCHWA-D患者的A β进行了生物化学和生物化学表征，以确定其在血管和实质沉积物中的长度。通过尺寸排阻凝胶色谱法纯化的甲酸可溶性淀粉样蛋白的质谱分析表明，A β 1-40及其羧基末端截短衍生物是软脑膜和皮质血管中的主要形式，A β 1-42是这些淀粉样蛋白提取物中的次要组分。分别对A β末端为瓦尔-40或Ala-42具有特异性的抗体S40和S42的免疫组织化学与来自血管淀粉样蛋白的生物化学数据一致。此外，实质类淀粉样病变被S42特异性染色，而未被S40标记，与AD、唐氏综合征和老年犬报道的模式一致。我们的结果表明，在HCHWA-D中，羧基末端A β异质性是由于体内有限的蛋白水解。他们提示，终止于Ala-42的A β种类对于淀粉样蛋白形成的播种和AD样神经炎变化的发展可能不是关键的。
In hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCEFWA-D), a genetic variant (E22Q) of amyloid beta (A beta) accumulates predominantly in the small vessels of leptomeninges and cerebral cortex, leading to fatal strokes in the fifth or sixth decade of life, A beta deposition in the neuropil occurs mainly in the form of preamyloid, Congo red negative deposits, while mature neuritic plaques and neurofibrillary tangles, hallmark lesions in Alzheimer's disease (AD), are characteristically absent, A recent hypothesis regarding the patho genesis of AD states that A beta extending to residues 42-43 (as opposed to shorter species) can seed amyloid formation and trigger the development of neuritic plaques followed by neuronal damage in AD. We characterized biochemically and immunohistochemically A beta from three cases of HCHWA-D to determine its length in vascular and parenchymal deposits, Mass spectrometry of formic acid-soluble amyloid, purified by size-exclusion gel chromatography, showed that A beta 1-40 and its carboxyl-terminal truncated derivatives were the predominant forms in leptomeningeal and cortical vessels, A beta 1-42 was a minor component in these amyloid extracts, Immunohistochemistry with antibodies S40 and S42, specific for A beta ending at Val-40 or Ala-42, respectively, were consistent with the biochemical data from vascular amyloid. In addition, parenchymal preamyloid lesions were specifically stained with S42 and were not labeled by S40, in agreement with the pattern reported for AD, Down's syndrome, and aged dogs, Our results suggest that in HCHWA-D the carboxyl-terminal A beta heterogeneity is due to limited proteolysis in vivo, Moreover, they suggest that A beta species ending at Ala-42 may not be critical for the seeding of amyloid formation and the development of AD-like neuritic changes.