Endosomal sorting of amyloid precursor protein-P-selectin chimeras influences secretase processing
Endosomal sorting of amyloid precursor protein-P-selectin chimeras influences secretase processing
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DOI：
10.1034/j.1600-0854.2001.21206.x
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发表时间：
2001-12-01
期刊：
影响因子：
4.5
通讯作者：
Green, SA
中科院分区：
文献类型：
--
作者：
Daugherty, BL;Green, SA
β淀粉样蛋白是阿尔茨海默病老年斑的主要成分，是通过淀粉样前体蛋白的分泌和内吞加工产生的。内化的淀粉样前体蛋白或者循环至α-分泌酶所在的质膜，或者移动至酸性室以暴露β-分泌酶。虽然反高尔基体网络含有 β 分泌酶活性，但最近对该蛋白酶（称为 BACE）的亚细胞分布的检查表明，β 分泌酶活性也可能存在于质膜和内体中。为了检查内吞区室在淀粉样前体蛋白的β-分泌酶加工中的作用，使用野生型和内体分选突变体P-选择素细胞质结构域来控制淀粉样前体蛋白通过内体的运动。淀粉样前体蛋白/P-选择素从早期内体分选到晚期内体，与淀粉样前体蛋白/P-选择素768A（一种更有效地循环至细胞表面的突变体）相比，其α-分泌酶裂解明显较少，而β-分泌酶裂解较多。我们的结果表明，内体分选影响淀粉样前体蛋白/P-选择素嵌合体对α和β-分泌酶活性的相对暴露，并表明，由于输送到晚期内吞区室有利于淀粉样前体蛋白的β-分泌酶加工，因此早期内体或细胞表面的β-分泌酶活性可能有限。我们认为跨高尔基体网络可能参与β淀粉样蛋白的分泌和内吞生成。
Amyloid beta protein, the major component of the senile plaques in Alzheimer's disease, is generated by secretory and endocytic processing of amyloid precursor protein. Internalized amyloid precursor protein either recycles to the plasma membrane, where alpha -secretase resides, or moves to acidic compartment(s) for beta -secretase exposure. While the trans-Golgi network contains beta -secretase activity, recent examination of the subcellular distribution of this proteinase, called BACE, has led to the suggestion that beta -secretase activity might also reside at the plasma membrane and in endosomes. To examine the role of endocytic compartments in beta -secretase processing of amyloid precursor protein, the wild-type and endosomal sorting mutant P-selectin cytoplasmic domains were used to control movement of amyloid precursor protein through endosomes. Amyloid precursor protein/P-selectin, which is sorted from early to late endosomes, undergoes significantly less a-secretase cleavage, and more beta -secretase cleavage, than amyloid precursor protein/P-selectin768A, a mutant that recycles more efficiently to the cell surface. Our results demonstrate that endosomal sorting influences relative exposure of the amyloid precursor protein/P-selectin chimeras to alpha- and beta -secretase activities, and suggest that, because delivery to late endocytic compartments favors beta -secretase processing of amyloid precursor protein, there is likely limited beta -secretase activity in early endosomes or at the cell surface. We propose that the trans-Golgi network may be involved in both secretory and endocytic generation of amyloid beta protein.