THE SWEDISH MUTATION CAUSES EARLY-ONSET ALZHEIMERS-DISEASE BY BETA-SECRETASE CLEAVAGE WITHIN THE SECRETORY PATHWAY
THE SWEDISH MUTATION CAUSES EARLY-ONSET ALZHEIMERS-DISEASE BY BETA-SECRETASE CLEAVAGE WITHIN THE SECRETORY PATHWAY
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DOI：
10.1038/nm1295-1291
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发表时间：
1995-12-01
期刊：
影响因子：
82.9
通讯作者：
SELKOE, DJ
中科院分区：
文献类型：
--
作者：
HAASS, C;LEMERE, CA;SELKOE, DJ
在β -淀粉样蛋白前体蛋白（β APP）的基因编码中，已经描述了几种导致早发性阿尔茨海默病（AD）的错义突变。在一个瑞典家庭中发现的双突变位于β APP的淀粉样β肽（A β）区域之前，导致A β的产生和分泌增加。在这里，我们发现A - β产生的增加是由细胞机制引起的，这与野生型β APP产生A - β的机制有很大的不同。在后一种情况下，β的产生需要β APP的再内化和再循环。在瑞典突变的情况下，A - β的n端β分泌酶切割发生在高尔基衍生囊泡中，最有可能发生在分泌囊泡中。因此，这种分裂与α -分泌酶的分裂发生在相同的腔室中，这通常会阻止α - β的产生，这解释了α -和β -分泌酶之间的竞争增加了α - β的产生。
Several missense mutations causing early-onset Alzheimer's disease (AD) have been described in the gene coding for the beta-amyloid precursor protein (beta APP). A double mutation found in a Swedish family is located before the amyloid beta-peptide (A beta) region of beta APP and results in the increased production and secretion of A beta. Here we show that the increased production of A beta results from a cellular mechanism, which differs substantially from that responsible for the production of A beta from wild-type beta APP. In the latter case, A beta generation requires reinternalization and recycling of beta APP. In the case of the Swedish mutation the N-terminal beta-secretase cleavage of A beta occurs in Golgi-derived vesicles, most likely within secretory vesicles. Therefore, this cleavage occurs in the same compartment as the alpha-secretase cleavage, which normally prevents A beta production,explaining the increased A beta generation by a competition between alpha- and beta-secretase.