ENZYMATICALLY ACTIVE LYSOSOMAL PROTEASES ARE ASSOCIATED WITH AMYLOID DEPOSITS IN ALZHEIMER BRAIN
ENZYMATICALLY ACTIVE LYSOSOMAL PROTEASES ARE ASSOCIATED WITH AMYLOID DEPOSITS IN ALZHEIMER BRAIN
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DOI：
10.1073/pnas.87.10.3861
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发表时间：
1990-05-01
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;NIXON, RA
β的形成-阿尔茨海默病患者脑中的淀粉样蛋白需要膜相关前体蛋白的蛋白水解裂解。可能参与该过程的蛋白酶尚未确定。组织蛋白酶通常是与溶酶体相关的细胞内蛋白水解酶;然而，当用组织蛋白酶D和组织蛋白酶B的抗血清对阿尔茨海默病脑切片进行染色时，在老年斑中也检测到高水平的免疫反应性。在年龄匹配的无神经系统疾病的个体或患有亨廷顿病或帕金森病的患者的对照脑中未观察到组织蛋白酶免疫反应性的细胞外位点。原位酶组织化学的组织蛋白酶D和组织蛋白酶B的部分新皮质使用合成肽和蛋白质底物显示，老年斑含有最高水平的酶活性组织蛋白酶。在超微结构水平上，老年斑中的组织蛋白酶免疫反应主要定位于细胞外的溶酶体致密体和脂褐素颗粒。在阿尔茨海默病新皮层的变性神经元中，类似的结构是丰富的，并且在一些老年斑中可以看到处于不同崩解阶段的载有组织蛋白酶的神经元胞体。高水平的酶活性溶酶体蛋白酶异常定位在老年斑代表候选酶的证据，可能介导的淀粉样蛋白的蛋白水解形成。我们认为老年斑内的淀粉样前体蛋白主要由退化神经元的溶酶体加工。组织蛋白酶从严格调控的细胞内环境中逃逸为积累的淀粉样前体蛋白的蛋白水解裂解的异常序列提供了基础。
The formation of .beta.-amyloid in the brains of individuals with Alzheimer disease requires the proteolytic cleavage of a membrane-associated precursor protien. The proteases that may be involved in this process have not yet been identified. Cathepsins are normally intracellular proteolytic enzymes associated with lysosomes; however, when sections from Alzheimer brains were stained by antisera to cathepsin D and cathepsin B, high levels of immunoreactivity were also detected in senile plaques. Extracellular sites of cathepsin immunoreactivity were not seen in control brains from age-matched individuals without neurologic disease or from patients with Huntington disease or Parkinson disease. In situ enzyme histochemistry of cathepsin D and cathepsin B on sections of neocortex using synthetic peptides and protein substrates showed that senile plaques contained the highest levels of enzymatically active cathepsin. At the ultrastructural level, cathepsin immunoreactivity in senile plaques was localized principally to lysosomal dense bodies and lipofuscin granules, which were extracellular. Similar structures were abundant in degeneration neurons of Alzheimer neocortex, and cathepsin-laden neuronal perikarya in various stages of disintegration could be seen within some senile plaques. The high levels of enzymatically competent lysosomal proteases abnormally localized in senile plaques represent evidence for candidate enzymes that may mediate the proteolytic formation of amyloid. We propose that amyloid precursor protein within senile plaques is processed by lysosomal principally derived from degenerating neurons. Escape of cathepsins from the stringently regulated intracellular milieu provides a basis for an abnormal sequence of proteolytic cleavages of accumulating amyloid precursor protein.