Presenilin-1 regulates intracellular trafficking and cell surface delivery of β-amyloid precursor protein

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

Research output: Contribution to journalArticlepeer-review

122 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3446-3454
Number of pages9
JournalJournal of Biological Chemistry
Volume278
Issue number5
DOIs
StatePublished - Jan 31 2003

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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