The role of γ-Secretase Activating Protein, GSAP and imatinib in the regulation of γ-secretase activity and amyloid-β generation.

Hussain I, Fabregue J, Anderes L, Ousson S, Borlat F, Eligert V, Berger S, Dimitrov M, Alattia JR, Fraering PC, Beher D.
Journal   J Biol Chem.
Species  
Analytes Measured   Abeta 40 , Abeta 42
Matrix Tested   Cell culture supernatants
Year   2012
Volume  
Page Numbers  
Application   Alzheimers
Abstract
γ-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 γ-secretase activating protein, GSAP was identified that interacts with γ-secretase and the C-terminal fragment of amyloid precursor protein to selectively increase amyloid-β production. In this study we have further characterised the role of endogenous and exogenous GSAP in the regulation of γ-secretase activity and amyloid-β production in vitro. Knockdown of GSAP expression in N2a cells decreased amyloid-β levels. In contrast, overexpression of GSAP in HEK cells expressing amyloid precursor protein or in N2a cells had no overt effect on amyloid-β generation. Likewise, purified recombinant GSAP had no effect on amyloid-β generation in two distinct in vitro γ-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-β 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, sub-chronic administration of imatinib to rats had no effect on brain amyloid-β levels. In summary, these findings suggest the roles of GSAP and imatinib in the regulation of γ-secretase activity and amyloid-β generation are uncertain.

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