Abstract | BACKGROUND: 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. 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.
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Authors | Kulandaivelu S Vetrivel, Ping Gong, James W Bowen, Haipeng Cheng, Ying Chen, Meghan Carter, Phuong D Nguyen, Lisa Placanica, Felix T Wieland, Yue-Ming Li, Maria Z Kounnas, Gopal Thinakaran |
Journal | Molecular neurodegeneration
(Mol Neurodegener)
Vol. 2
Pg. 4
(Feb 08 2007)
ISSN: 1750-1326 [Electronic] England |
PMID | 17288597
(Publication Type: Journal Article)
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