Presenilin-1 Regulates Intracellular Trafficking and Cell Surface Delivery of β-Amyloid Precursor Protein

Presenilins (PS1/PS2) play a critical role in proteolysis of β-amyloid precursor protein (βAPP) to generate β-amyloid, a peptide important in the pathogenesis of Alzheimer's disease. Nevertheless, several regulatory functions of PS1 have also been reported. Here we demonstrate, in neuroblast...

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Bibliographic Details
Published in:The Journal of biological chemistry 2003-01, Vol.278 (5), p.3446
Main Authors: Dongming Cai, Jae Yoon Leem, Jeffrey P. Greenfield, Pei Wang, Benny S. Kim, Runsheng Wang, Kryslaine O. Lopes, Seong-Hun Kim, Hui Zheng, Paul Greengard, Sangram S. Sisodia, Gopal Thinakaran, Huaxi Xu
Format: Article
Language:English
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Summary:Presenilins (PS1/PS2) play a critical role in proteolysis of β-amyloid precursor protein (βAPP) to generate β-amyloid, a peptide important in the pathogenesis of Alzheimer's disease. Nevertheless, several regulatory functions of PS1 have also been reported. Here we demonstrate, in neuroblastoma cells, that PS1 regulates the biogenesis of βAPP-containing vesicles from the trans -Golgi network and the endoplasmic reticulum. PS1 deficiency or the expression of loss-of-function variants leads to robust vesicle formation, concomitant with increased maturation and/or cell surface accumulation of βAPP. In contrast, release of vesicles containing βAPP is impaired in familial Alzheimer's disease (FAD)-linked PS1 mutant cells, resulting in reduced βAPP delivery to the cell surface. Moreover, diminution of surface βAPP is profound at axonal terminals in neurons expressing a PS1 FAD variant. These results suggest that PS1 regulation of βAPP trafficking may represent an alternative mechanism by which FAD-linked PS1 variants modulate βAPP processing.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M209065200