Truncated carboxyl-terminal fragments of β-amyloid precursor protein are processed to amyloid β-proteins 40 and 42
Truncated carboxyl-terminal fragments of β-amyloid precursor protein are processed to amyloid β-proteins 40 and 42
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DOI：
10.1021/bi049399k
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发表时间：
2004-10-26
期刊：
影响因子：
2.9
通讯作者：
Ihara, Y
中科院分区：
文献类型：
--
作者：
Funamoto, S;Morshima-Kawashima, M;Ihara, Y
我们以前发现，β-淀粉样前体蛋白(APP)不仅在膜的中央被切割(伽马切割)，而且在靠近膜/细胞质边界的新的切割位置(epsilon切割)，释放APP胞内域(AICD)49-99和50-99。为了进一步了解γ-和epsilon-裂解之间的关系，在CHO细胞中瞬时表达了APP的C端截短的羧基末端片段，特别是CTFs1-48和1-49(推测的产物是由epsilon-裂解产生的)。最重要的是，表达CTFI-49的细胞主要分泌淀粉样β蛋白(Abeta)40，而表达CTF1-48的细胞主要分泌Abeta42。这支持了我们的假设，即c-裂解先于Abeta产生，而之前的epsilon-裂解决定了对最终Abeta物种的偏好。伽玛分泌酶抑制剂L-685,458和DAPT抑制CTF1-49产生Abeta。关于CTF1-48的Abeta生产，L-685,458抑制了它，但DAPT没有这样做。早老素1的显性负性突变体抑制了CTFs1-48和1-49产生的Abeta40和42。这些数据应该会对Abeta产生的机制有重要的帮助。
We previously showed that beta-amyloid precursor protein (APP) is cleaved not only in the middle of the membrane (gamma-cleavage) but also at novel cleavage sites close to the membrane/cytoplasmic boundary (epsilon-cleavage), releasing APP intracellular domains (AICDs) 49-99 and 50-99. To learn more about the relationship between gamma- and epsilon-cleavage, C-terminally truncated carboxyl-terminal fragments (CTFs) of APP, especially CTFs1-48 and 1-49 (the postulated products that are generated by epsilon-cleavage), were transiently expressed in CHO cells. Most importantly, the cells expressing CTFI-49 secreted predominantly amyloid beta-protein (Abeta) 40, while those expressing CTF1-48 secreted preferentially Abeta42. This supports our assumption that c-cleavage precedes Abeta production and that preceding epsilon-cleavage determines the preference for the final Abeta species. The gamma-secretase inhibitors, L-685,458 and DAPT, suppressed Abeta production from CTF1-49. Regarding Abeta production from CTF1-48, L-685,458 suppressed it, but DAPT failed to do so. A dominant negative mutant of presenilin 1 suppressed the production of Abeta40 and 42 from both CTFs1-48 and 1-49. These data should shed significant light into the mechanism of Abeta production.