PROCESSING OF ALZHEIMER BETA-A4 AMYLOID PRECURSOR PROTEIN - MODULATION BY AGENTS THAT REGULATE PROTEIN-PHOSPHORYLATION
PROCESSING OF ALZHEIMER BETA-A4 AMYLOID PRECURSOR PROTEIN - MODULATION BY AGENTS THAT REGULATE PROTEIN-PHOSPHORYLATION
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DOI：
10.1073/pnas.87.15.6003
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发表时间：
1990-08-01
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;GANDY, SE;GREENGARD, P
阿尔茨海默氏病β/已经在用调节蛋白磷酸化的试剂处理后的PC 12细胞中研究了A4淀粉样前体蛋白（β APP）。佛波醇12，13-二丁酸酯，一种刺激蛋白激酶C的试剂，降低了成熟β APP的水平并增加了15-和19-kDa肽的水平。这些肽似乎是β APP的COOH-末端片段，当佛波醇12，13-二丁酸酯增加β APP成熟形式的蛋白水解加工速率时产生。冈田酸（蛋白磷酸酶1和2A的抑制剂）也导致成熟β APP水平的降低和15-和19-kDa肽水平的增加。H-7，蛋白激酶C和几种其它蛋白激酶的抑制剂，明显降低了成熟β APP的蛋白水解加工速率。用佛波醇12，13-二丁酸酯或冈田酸处理后观察到的推定的COOH-末端片段的大小表明，一种或两种可能含有完整的β APP。β APP的A4区，因此是淀粉样蛋白生成的。我们的研究结果支持这样的假说，即异常的蛋白磷酸化可能在伴随阿尔茨海默病的脑淀粉样变性的发展中起作用。
The turnover and processing of the Alzheimer .beta./A4 amyloid precursor protein (.beta.APP) has been studied in PC12 cells after treatment with agents that regulate protein phosphorylation. Phorbol 12,13-dibutyrate, an agent that stimulates protein kinase C, decreased the levels of mature .beta.APP and increased the levels of 15- and 19-kDa peptides. These peptides appeared to be COOH-terminal fragments of .beta.APP, which arose when phorbol 12,13-dibutyrate increased the rate of proteolytic processing of mature forms of .beta.APP. Okadaic acid, an inhibitor of protein phosphatases 1 and 2A, also led to decreased levels of mature .beta.APP and increased levels of the 15- and 19-kDa peptides. H-7, an inhibitor of protein kinase C and of several other protein kinases, apparently decreased the rate of proteolytic processing of mature .beta.APP. The size of the putative COOH-terminal fragments observed after treatment with either phorbol 12,13-dibutyrate or okadaic acid suggest that one or both may contain the entire .beta./A4 region of .beta.APP and thus be amyloidogenic. Our results support the hypotehsis that abnormal protein phosphorylation may play a role in the development of the cerebral amyloidosis that accompanies Alzheimer disease.