Differential regulation of amyloid precursor protein sorting with pathological mutations results in a distinct effect on amyloid-β production

被引：11

作者：

Lin, Yen-Chen ^{[1
,2
]}

Wang, Jia-Yi ^{[1
]}

Wang, Kai-Chen ^{[3
,4
]}

Liao, Jhih-Ying ^{[1
]}

Cheng, Irene H. ^{[1
,2
,5
,6
,7
]}

机构：

[1] Natl Yang Ming Univ, Inst Brain Sci, Taipei 11221, Taiwan

[2] Acad Sinica, Taiwan Int Grad Program, Taipei 115, Taiwan

[3] Cheng Hsin Gen Hosp, Taipei, Taiwan

[4] Natl Yang Ming Univ, Sch Med, Taipei 11221, Taiwan

[5] Natl Yang Ming Univ, Brain Res Ctr, Taipei 11221, Taiwan

[6] Natl Yang Ming Univ, Infect & Immun Res Ctr, Taipei 11221, Taiwan

[7] Taipei Vet Gen Hosp, Immunol Ctr, Taipei, Taiwan

来源：

JOURNAL OF NEUROCHEMISTRY | 2014年 / 131卷 / 04期

关键词：

Alzheimer's disease; amyloid-beta; amyloid precursor protein; familial mutations; FAMILIAL ALZHEIMERS-DISEASE; APP; PATHOGENESIS; TRAFFICKING; BACE; ENDOCYTOSIS; GENERATION; VARIANTS; PATHWAYS; DEMENTIA;

D O I：

10.1111/jnc.12829

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The deposition of amyloid-beta (A beta) peptide, which is generated from amyloid precursor protein (APP), is the pathological hallmark of Alzheimer's disease (AD). Three APP familial AD mutations (D678H, D678N, and H677R) located at the sixth and seventh amino acid of A beta have distinct effect on A beta aggregation, but their influence on the physiological and pathological roles of APP remain unclear. We found that the D678H mutation strongly enhances amyloidogenic cleavage of APP, thus increasing the production of A beta. This enhancement of amyloidogenic cleavage is likely because of the acceleration of APP(D678H) sorting into the endosomal-lysosomal pathway. In contrast, the APP(D678N) and APP(H677R) mutants do not cause the same effects. Therefore, this study indicates a regulatory role of D678H in APP sorting and processing, and provides genetic evidence for the importance of APP sorting in AD pathogenesis.

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收藏

页码：407 / 412

页数：6

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