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

doi:10.1074/jbc.m209065200

Dongming Cai, Jae Yoon Leem + Show 11 more

Open Access

https://doi.org/10.1074/jbc.m209065200

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Abstract

Presenilins (PS1/PS2) play a critical role in proteolysis of beta-amyloid precursor protein (beta APP) to generate beta-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 beta APP-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 beta APP. In contrast, release of vesicles containing beta APP is impaired in familial Alzheimer's disease (FAD)-linked PS1 mutant cells, resulting in reduced beta APP delivery to the cell surface. Moreover, diminution of surface beta APP is profound at axonal terminals in neurons expressing a PS1 FAD variant. These results suggest that PS1 regulation of beta APP trafficking may represent an alternative mechanism by which FAD-linked PS1 variants modulate beta APP processing.

Highlights

Presenilins (PS1/presenilin 2 (PS2)) play a critical role in proteolysis of ␤-amyloid precursor protein (␤APP) to generate ␤-amyloid, a peptide important in the pathogenesis of Alzheimer’s disease
presenilin 1 (PS1) Deficiency Leads to Increased ␤APP Transport from trans-Golgi network (TGN) to Plasma Membrane and from endoplasmic reticulum (ER) to Golgi—It has been well established that PS1-deficient neurons fail to secrete A␤ but accumulate intracellular ␤APP C-terminal fragments (25, 40)
To ascertain the selectivity of impaired ␤APP-containing vesicle budding in cells expressing familial Alzheimer’s disease (FAD)-linked PS1 variants, we examined the trafficking of neural cell adhesion molecule (NCAM) from the TGN using the permeabilized cell system

Summary

Introduction

Presenilins (PS1/PS2) play a critical role in proteolysis of ␤-amyloid precursor protein (␤APP) to generate ␤-amyloid, a peptide important in the pathogenesis of Alzheimer’s disease. We report here that PS1 deficiency or expression of loss-of-function variants led to robust formation of ␤APP-containing vesicles, concomitant with increased maturation and/or cell surface accumulation of ␤APP.

Results

Conclusion