The role of ?-secretase activating protein (GSAP) and imatinib in the regulation of ?-secretase activity and amyloid-? generation.
?-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 ?-secretase activating protein (GSAP) was identified that interacts with ?-secretase and the C-terminal fragment ... of amyloid precursor protein to selectively increase amyloid-? production. In this study we have further characterized the role of endogenous and exogenous GSAP in the regulation of ?-secretase activity and amyloid-? production in vitro. Knockdown of GSAP expression in N2a cells decreased amyloid-? levels. In contrast, overexpression of GSAP in HEK cells expressing amyloid precursor protein or in N2a cells had no overt effect on amyloid-? generation. Likewise, purified recombinant GSAP had no effect on amyloid-? generation in two distinct in vitro ?-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-? 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-? levels. In summary, these findings suggest the roles of GSAP and imatinib in the regulation of ?-secretase activity and amyloid-? generation are uncertain.
Mesh Terms:
Alzheimer Disease, Amyloid Precursor Protein Secretases, Amyloid beta-Peptides, Animals, Benzamides, Brain, Cell Line, Tumor, Gene Expression Regulation, Humans, Imatinib Mesylate, Male, Mice, Piperazines, Protein Binding, Protein Kinase Inhibitors, Proteins, Pyrimidines, RNA, Small Interfering, Rats, Rats, Sprague-Dawley, Recombinant Proteins
Alzheimer Disease, Amyloid Precursor Protein Secretases, Amyloid beta-Peptides, Animals, Benzamides, Brain, Cell Line, Tumor, Gene Expression Regulation, Humans, Imatinib Mesylate, Male, Mice, Piperazines, Protein Binding, Protein Kinase Inhibitors, Proteins, Pyrimidines, RNA, Small Interfering, Rats, Rats, Sprague-Dawley, Recombinant Proteins
J. Biol. Chem.
Date: Jan. 25, 2013
PubMed ID: 23209290
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