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Small‐molecule inducers of Aβ‐42 peptide production share a common mechanism of action
Author(s) -
Bettayeb Karima,
Oumata Nassima,
Zhang Yuanyuan,
Luo Wenjie,
Bustos Victor,
Galons Hervé,
Greengard Paul,
Meijer Laurent,
Flajolet Marc
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.12-212985
Subject(s) - vdac1 , mechanism of action , peptide , chemistry , small molecule , microbiology and biotechnology , biochemistry , in vitro , biology , gene , escherichia coli , bacterial outer membrane
The pathways leading specifically to the toxic Aβ42 peptide production, a key event in Alzheimer's disease (AD), are unknown. While searching for pathways that mediate pathological increases of Aβ42, we identified Aftin‐4, a new compound that selectively and potently increases Aβ42 compared to DMSO (N2a cells: 7‐fold; primary neurons: 4‐fold; brain lysates: 2‐fold) with an EC 50 of 30 μM. 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 γ‐secretase components and could, therefore, modify γ‐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 Aβ42 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 Aβ‐42 peptide production share a common mechanism of action. FASEB J. 26, 5115–5123 (2012). www.fasebj.org

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