Research article

Dual roles of the transmembrane protein p23/TMP21 in the modulation of amyloid precursor protein metabolism

Kulandaivelu S Vetrivel^1* , Ping Gong^1* , James W Bowen^2* , Haipeng Cheng¹ , Ying Chen¹ , Meghan Carter¹ , Phuong D Nguyen³ , Lisa Placanica⁴ , Felix T Wieland⁵ , Yue-Ming Li⁴ , Maria Z Kounnas³ and Gopal Thinakaran^1,2

¹  Departments of Neurobiology and Neurology, The University of Chicago, Chicago, IL 60637, USA

²  Committee on Neurobiology, The University of Chicago, Chicago, IL 60637, USA

³  TorreyPines Therapeutics, Inc. La Jolla, CA 92037, USA

⁴  Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA

⁵  Biochemie-Zentrum der Universitat Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany

author email corresponding author email* Contributed equally

Molecular Neurodegeneration 2007, 2:4doi:10.1186/1750-1326-2-4

Published:	8 February 2007

Abstract

Background

Alzheimer's disease (AD) is characterized by cerebral deposition of β-amyloid (Aβ) peptides. Aβ is released from ectodomain cleaved amyloid precursor protein (APP) via intramembranous proteolysis by γ-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 γ-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 Aβ production increases following p23 knockdown, similar to data reported earlier using HEK293 cells. However, we find that p23 is not present in mature γ-secretase complexes isolated using an active-site γ-secretase inhibitor. Depletion of p23 and expression of a familial AD-linked PS1 mutant have additive effects on Aβ₄₂ 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 γ-secretase modulation.

Conclusion

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.