Small-molecule inducers of A beta-42 peptide production share a common mechanism of action

Article

关键词: FAMILIAL ALZHEIMERS-DISEASE;    AMYLOID-BETA;    LIPID RAFTS;    GAMMA-SECRETASE;    SENILE PLAQUES;    IN-VIVO;    PROTEIN;    BRAIN;    IDENTIFICATION;    MUTATIONS;   

DOI  :  10.1096/fj.12-212985

来源: SCIE

【 摘 要 】

The pathways leading specifically to the toxic A beta 42 peptide production, a key event in Alzheimer's disease (AD), are unknown. While searching for pathways that mediate pathological increases of A beta 42, we identified Aftin-4, a new compound that selectively and potently increases A beta 42 compared to DMSO (N2a cells: 7-fold; primary neurons: 4-fold; brain lysates: 2-fold) with an EC50 of 30 mu M. These results were confirmed by ELISA and IP-WB. Using affinity chromatography and mass spectrometry, we identified 3 proteins (VDAC1, prohibitin, and mitofilin) relevant to AD that interact with Aftin-4, but not with a structurally similar but inactive molecule. Electron microscopy studies demonstrated that Aftin-4 induces a reversible mitochondrial phenotype reminiscent of the one observed in AD brains. Sucrose gradient fractionation showed that Aftin-4 perturbs the subcellular localization of gamma-secretase components and could, therefore, modify gamma-secretase specificity by locally altering its membrane environment. Remarkably, Aftin-4 shares all these properties with two other AD accelerator compounds. In summary, treatment with three A beta 42 raising agents induced similar biochemical alterations that lead to comparable cellular phenotypes in vitro, suggesting a common mechanism of action involving three structural cellular targets.-Bettayeb, K., Oumata, N., Zhang, Y., Luo, W., Bustos, V., Galons, H., Greengard, P., Meijer, L., Flajolet, M. Small-molecule inducers of A beta-42 peptide production share a common mechanism of action. FASEB J. 26, 5115-5123 (2012). www.fasebj.org

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