LYSOSOMAL HYDROLASES OF DIFFERENT CLASSES ARE ABNORMALLY DISTRIBUTED IN BRAINS OF PATIENTS WITH ALZHEIMER-DISEASE
LYSOSOMAL HYDROLASES OF DIFFERENT CLASSES ARE ABNORMALLY DISTRIBUTED IN BRAINS OF PATIENTS WITH ALZHEIMER-DISEASE
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DOI：
10.1073/pnas.88.24.10998
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发表时间：
1991-12-01
影响因子：
11.1
通讯作者：
NIXON, RA
中科院分区：
文献类型：
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作者：
CATALDO, AM;PASKEVICH, PA;NIXON, RA
β -淀粉样蛋白的形成需要淀粉样蛋白前体蛋白（APP）的多次异常蛋白水解裂解，包括其膜内结构域的一次裂解。溶酶体含有多种蛋白酶（组织蛋白酶）和其他酸水解酶，是膜蛋白和其他细胞成分周转的主要位点。利用免疫细胞化学、免疫电镜和酶组织化学技术，我们研究了阿尔茨海默病患者和对照组（非阿尔茨海默病患者）新皮层中10种溶酶体水解酶的表达和细胞分布，其中包括4种组织蛋白酶。在对照大脑中，酸水解酶仅局限于细胞内溶酶体相关的室室，10种酶中的8种在神经元中占主导地位。在阿尔茨海默病患者的大脑中，许多皮质神经元的核周和近端树突明显积聚了强烈的免疫反应性溶酶体和脂褐素颗粒，其中一些正在变性。更引人注目的是，在阿尔茨海默病的老年斑中，这些水解酶的含量同样高或更高，但在对照组大脑的细胞外却没有发现它们，包括帕金森病或亨廷顿病患者的大脑。在超微结构水平上，老年斑的水解酶免疫反应性定位于细胞外脂褐质颗粒，其形态与退行性神经元内的颗粒相似。老年斑中不存在神经元中检测不到的两种组织蛋白酶。这些结果表明，阿尔茨海默病皮质神经元的溶酶体功能发生了改变。老年斑中酸性水解酶的广谱存在表明，溶酶体及其内容物可能在细胞（主要是神经元及其过程）退化时从细胞中释放出来。因为组织蛋白酶可以切割APP上与β -淀粉样蛋白形成相关的多肽位点，它们在阿尔茨海默病中的异常细胞外定位和失调可以解释β -淀粉样蛋白形成过程中的多重水解事件。膜降解酸水解酶的作用也可以解释含有β -淀粉样蛋白C端的APP膜内部分如何被蛋白酶接近。
Beta-amyloid formation requires multiple abnormal proteolytic cleavages of amyloid precursor protein (APP), including one within its intramembrane domain. Lysosomes, which contain a wide variety of proteases (cathepsins) and other acid hydrolases, are major sites for the turnover of membrane proteins and other cell constituents. Using immunocytochemistry, immunoelectron microscopy, and enzyme histochemistry, we studied the expression and cellular distributions of 10 lysosomal hydrolases, including 4 cathepsins, in neocortex from patients with Alzheimer disease and control (non-Alzheimer-disease) individuals. In control brains, acid hydrolases were localized exclusively to intracellular lysosome-related compartments, and 8 of the 10 enzymes predominated in neurons. In Alzheimer disease brains, strongly immunoreactive lysosomes and lipofuscin granules accumulated markedly in the perikarya and proximal dendrites of many cortical neurons, some of which were undergoing degeneration. More strikingly, these same hydrolases were present in equally high or higher levels in senile plaques in Alzheimer disease, but they were not found extracellularly in control brains, including those from Parkinson or Huntington disease patients. At the ultrastructural level, hydrolase immunoreactivity in senile plaques was localized to extracellular lipofuscin granules similar in morphology to those within degenerating neurons. Two cathepsins that were undetectable in neurons were absent from senile plaques. These results show that lysosome function is altered in cortical neurons in Alzheimer disease. The presence of a broad spectrum of acid hydrolases in senile plaques indicates that lysosomes and their contents may be liberated from cells, principally neurons and their processes, as they degenerate. Because cathepsins can cleave polypeptide sites on APP relevant for beta-amyloid formation, their abnormal extracellular localization and dysregulation in Alzheimer disease can account for the multiple hydrolytic events in beta-amyloid formation. The actions of membrane-degrading acid hydrolases could also explain how the intramembrane portion of APP containing the C terminus of beta-amyloid becomes accessible to proteases.