Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 288, Issue 4, Pages 2521-2531Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M112.370924
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Funding
- Swiss National Science Foundation Grant [31003A_134938/1]
- Ecole Polytechnique Federale de Lausanne (EPFL)-Merck Serono grant
- Swiss National Science Foundation (SNF) [31003A_134938] Funding Source: Swiss National Science Foundation (SNF)
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gamma-Secretase is a large enzyme complex comprising presenilin, nicastrin, presenilin enhancer 2, and anterior pharynx-defective 1 that mediates the intramembrane proteolysis of a large number of proteins including amyloid precursor protein and Notch. Recently, a novel gamma-secretase activating protein (GSAP) was identified that interacts with gamma-secretase and the C-terminal fragment of amyloid precursor protein to selectively increase amyloid-beta production. In this study we have further characterized the role of endogenous and exogenous GSAP in the regulation of gamma-secretase activity and amyloid-beta production in vitro. Knockdown of GSAP expression in N2a cells decreased amyloid-beta levels. In contrast, overexpression of GSAP in HEK cells expressing amyloid precursor protein or in N2a cells had no overt effect on amyloid-beta generation. Likewise, purified recombinant GSAP had no effect on amyloid-beta generation in two distinct in vitro gamma-secretase assays. In subsequent cellular studies with imatinib, a kinase inhibitor that reportedly prevents the interaction of GSAP with the C-terminal fragment of amyloid precursor protein, a concentration-dependent decrease in amyloid-beta levels was observed. However, no interaction between GSAP and the C-terminal fragment of amyloid precursor protein was evident in co-immunoprecipitation studies. In addition, subchronic administration of imatinib to rats had no effect on brain amyloid-beta levels. In summary, these findings suggest the roles of GSAP and imatinib in the regulation of gamma-secretase activity and amyloid-beta generation are uncertain.
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