期刊
BMC CELL BIOLOGY
卷 6, 期 -, 页码 -出版社
BMC
DOI: 10.1186/1471-2121-6-30
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资金
- Intramural NIH HHS [Z01 AG000115] Funding Source: Medline
- NIA NIH HHS [T32 AG000115] Funding Source: Medline
- NIMH NIH HHS [R01 MH059775, MH59775] Funding Source: Medline
- NINDS NIH HHS [NS30791] Funding Source: Medline
Background: The amyloid precursor protein ( APP) is transported via the secretory pathway to the cell surface, where it may be cleaved within its ectodomain by alpha-secretase, or internalized within clathrin-coated vesicles. An alternative proteolytic pathway occurs within the endocytic compartment, where the sequential action of beta- and gamma-secretases generates the amyloid beta protein (A beta). In this study, we investigated the effects of modulators of endocytosis on APP processing. Results: Human embryonic kidney cells were transfected with a dominant negative mutant of dynamin I, an important mediator of clathrin-dependent endocytosis, and APP proteolysis was analyzed. Overexpression of the mutant dynamin (dyn I K44A) resulted in increased shedding of the APP ectodomain (sAPP alpha), accumulation of the C-terminal alpha-secretase product C83, and a reduction in the release of A beta. Levels of mature APP on the cell surface were increased in cells expressing dyn I K44A, and internalization of surface-immunolabeled APP, assessed by fluorescence microscopy, was inhibited. Dynamin is a substrate for protein kinase C ( PKC), and it was hypothesized that activators of PKC, which are known to stimulate alpha-secretase-mediated cleavage of APP, might exert their effects by inhibiting dynamin-dependent endocytosis. However, the internalization of surface-biotinylated APP was unaffected by treatment of cells with phorbol 12-myristate 13-acetate in the presence of the alpha-secretase inhibitor TAPI-1. Conclusion: The results indicate that APP is internalized by a dynamin-dependent process, and suggest that alterations in the activity of proteins that mediate endocytosis might lead to significant changes in A beta production.
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