PROTEIN-PHOSPHORYLATION INHIBITS PRODUCTION OF ALZHEIMER AMYLOID-BETA/A4 PEPTIDE
PROTEIN-PHOSPHORYLATION INHIBITS PRODUCTION OF ALZHEIMER AMYLOID-BETA/A4 PEPTIDE
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DOI：
10.1073/pnas.90.19.9195
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发表时间：
1993-10-01
影响因子：
11.1
通讯作者：
GREENGARD, P
中科院分区：
文献类型：
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作者：
BUXBAUM, JD;KOO, EH;GREENGARD, P
在阿尔茨海默病中发现的淀粉样斑块核心和脑血管淀粉样沉积物的主要成分是β/A4肽，其来源于阿尔茨海默淀粉样蛋白前体（APP）。最近的证据表明β/A4肽产生或β/A4肽聚集的异常可能是脑淀粉样变性的基础。在本研究中，用激活蛋白激酶C的佛波醇二丁酸酯和/或抑制蛋白磷酸酶1和2A的冈田酸处理细胞，使β/A4肽的产生减少50- 80%。在稳定转染的CHO细胞中表达的APP 695和APP 751以及人胶质瘤（Hs 683）细胞中的内源性APP中观察到这些效应。佛波醇二丁酸酯还降低表达与家族性阿尔茨海默病相关的APP的各种突变形式的细胞中的β/A4肽产生，据报道其中一种突变形式在培养细胞中表现出极大增加的β/A4肽产生。Mastoparan和mastoparan X（可激活磷脂酶C并因此激活蛋白激酶C的化合物）也可降低用APP 695稳定转染的CHO细胞中β/A4肽的产生。一个模型中，β/A4肽生产的减少，可以通过加速APP的代谢通过nonamyloidogenic分泌途径来实现。
The major component of amyloid plaque cores and cerebrovascular amyloid deposits found in Alzheimer disease is the beta/A4 peptide, which is derived from the Alzheimer amyloid protein precursor (APP). Recent evidence suggests that abnormalities in beta/A4 peptide production or beta/A4 peptide aggregation may underlie cerebral amyloidosis. In the present study, treatment of cells with phorbol dibutyrate, which activates protein kinase C, and/or okadaic acid, which inhibits protein phosphatases 1 and 2A, reduced beta/A4 peptide production by 50-80%. These effects were observed with APP695 and APP751 expressed in stably transfected CHO cells, as well as with endogenous APP in human glioma (Hs 683) cells. Phorbol dibutyrate also decreased beta/A4 peptide production in cells expressing various mutant forms of APP associated with familial Alzheimer disease, one of which was reported to manifest greatly increased beta/A4 peptide production in cultured cells. Mastoparan and mastoparan X, compounds which can activate phospholipase C and hence protein kinase C, also decreased beta/A4 peptide production in CHO cells stably transfected with APP695. A model is presented in which decreases in beta/A4 peptide production can be achieved by accelerating the metabolism of APP through a nonamyloidgenic secretory pathway.