Dual roles of the transmembrane protein p23/TMP21 in the modulation of amyloid precursor protein metabolism.
BACKGROUND
Alzheimer's disease (AD) is characterized by cerebral deposition of beta-amyloid (Abeta) peptides. Abeta is released from ectodomain cleaved amyloid precursor protein (APP) via intramembranous proteolysis by gamma-secretase, a complex consisting of presenilin and a few other proteins. p23/TMP21, a member of the p24 family type I transmembrane proteins, was recently identified as a presenilin complex component capable of modulating gamma-secretase cleavage. The p24 family proteins form oligomeric complexes and regulate vesicular trafficking in the early secretory pathway, but their role in APP trafficking has not been investigated.


RESULTS
Here, we report that siRNA-mediated depletion of p23 in N2a neuroblastoma and HeLa cells produces concomitant knockdown of additional p24 family proteins and increases secretion of sAPP. Furthermore, intact cell and cell-free Abeta production increases following p23 knockdown, similar to data reported earlier using HEK293 cells. However, we find that p23 is not present in mature gamma-secretase complexes isolated using an active-site gamma-secretase inhibitor. Depletion of p23 and expression of a familial AD-linked PS1 mutant have additive effects on Abeta42 production. Knockdown of p23 expression confers biosynthetic stability to nascent APP, allowing its efficient maturation and surface accumulation. Moreover, immunoisolation analyses show decrease in co-residence of APP and the APP adaptor Mint3. Thus, multiple lines of evidence indicate that p23 function influences APP trafficking and sAPP release independent of its reported role in gamma-secretase modulation.


CONCLUSIONS
These data assign significance to p24 family proteins in regulating APP trafficking in the continuum of bidirectional transport between the ER and Golgi, and ascribe new relevance to the regulation of early trafficking in AD pathogenesis.
Vetrivel
Kulandaivelu S
KS
Department of Neurobiology, The University of Chicago, Chicago, IL 60637, USA. vetrivel@uchicago.edu
Gong
Ping
P
Bowen
James W
JW
Cheng
Haipeng
H
Chen
Ying
Y
Carter
Meghan
M
Nguyen
Phuong D
PD
Placanica
Lisa
L
Wieland
Felix T
FT
Li
Yue-Ming
YM
Kounnas
Maria Z
MZ
Thinakaran
Gopal
G