Presenilin-1 regulates intracellular trafficking and cell surface delivery of beta-amyloid precursor protein.
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.
Cai
Dongming
D
Fisher Center for Research on Alzheimer's Disease and Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York 10021, USA.
Leem
Jae Yoon
JY
Greenfield
Jeffrey P
JP
Wang
Pei
P
Kim
Benny S
BS
Wang
Runsheng
R
Lopes
Kryslaine O
KO
Kim
Seong-Hun
SH
Zheng
Hui
H
Greengard
Paul
P
Sisodia
Sangram S
SS
Thinakaran
Gopal
G
Xu
Huaxi
H
D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019921:Biotinylation; D002462:Cell Membrane / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018613:Microscopy, Confocal; D008954:Models, Biological; D009447:Neuroblastoma; D053764:Presenilin-1; D021381:Protein Transport; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D021601:trans-Golgi Network / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D011994:Recombinant Proteins