α-secretase mediated conversion of the amyloid precursor protein derived membrane stub C99 to C83 limits Aβ generation
α-secretase mediated conversion of the amyloid precursor protein derived membrane stub C99 to C83 limits Aβ generation
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DOI：
10.1111/j.1471-4159.2009.06420.x
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发表时间：
2009-12-01
影响因子：
4.7
通讯作者：
Pietrzik, Claus U.
中科院分区：
文献类型：
--
作者：
Jaeger, Sebastian;Leuchtenberger, Stefanie;Pietrzik, Claus U.
淀粉样前体蛋白（APP）内的瑞典突变由于BACE 1对APP的切割增加而导致早发性阿尔茨海默病。虽然瑞典APP（APPswe）的β-分泌酶脱落主要是由于定位于晚期分泌途径的活性，但野生型APP的裂解主要发生在内吞隔室中。然而，我们发现，从APPswe释放A β仍然依赖于从细胞表面的功能内化。尽管从APP（swe）分泌释放的β-分泌酶切割的可溶性APP总体上不变，但APP swe内化基序的突变强烈降低了C99水平并显著降低了A β分泌。我们指出，α-分泌酶活性介导的C99转化为C83是A β减少的主要原因。此外，我们证明α-分泌酶切割C99甚至有助于减少内化缺陷野生型APP的A β分泌。因此，抑制α-分泌酶切割通过减少APP 695、APP 695 swe或C99表达细胞中C99向C83的转化来增加A β分泌。
The Swedish mutation within the amyloid precursor protein (APP) causes early-onset Alzheimer's disease due to increased cleavage of APP by BACE1. While beta-secretase shedding of Swedish APP (APPswe) largely results from an activity localized in the late secretory pathway, cleavage of wild-type APP occurs mainly in endocytic compartments. However, we show that liberation of A beta from APPswe is still dependent on functional internalization from the cell surface. Inspite the unchanged overall beta-secretase cleaved soluble APP released from APP(swe) secretion, mutations of the APPswe internalization motif strongly reduced C99 levels and substantially decreased A beta secretion. We point out that alpha-secretase activity-mediated conversion of C99 to C83 is the main cause of this A beta reduction. Furthermore, we demonstrate that alpha-secretase cleavage of C99 even contributes to the reduction of A beta secretion of internalization deficient wild-type APP. Therefore, inhibition of alpha-secretase cleavage increased A beta secretion through diminished conversion of C99 to C83 in APP695, APP695swe or C99 expressing cells.