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A Novel Inhibitor of Amyloid β (Aβ) Peptide Aggregation

Author(s): McKoy, Angela Fortner; Chen, Jermont; Schupbach, Trudi; Hecht, Michael H.

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Abstract: Compelling evidence indicates that aggregation of the amyloid β (Aβ) peptide is a major underlying molecular culprit in Alzheimer disease. Specifically, soluble oligomers of the 42-residue peptide (Aβ42) lead to a series of events that cause cellular dysfunction and neuronal death. Therefore, inhibiting Aβ42 aggregation may be an effective strategy for the prevention and/or treatment of disease. We describe the implementation of a high throughput screen for inhibitors of Aβ42 aggregation on a collection of 65,000 small molecules. Among several novel inhibitors isolated by the screen, compound D737 was most effective in inhibiting Aβ42 aggregation and reducing Aβ42-induced toxicity in cell culture. The protective activity of D737 was most significant in reducing the toxicity of high molecular weight oligomers of Aβ42. The ability of D737 to prevent Aβ42 aggregation protects against cellular dysfunction and reduces the production/accumulation of reactive oxygen species. Most importantly, treatment with D737 increases the life span and locomotive ability of flies in a Drosophila melanogaster model of Alzheimer disease.
Publication Date: 9-Nov-2012
Electronic Publication Date: 19-Sep-2012
Citation: McKoy, Angela Fortner, Chen, Jermont, Schupbach, Trudi, Hecht, Michael H. (2012). A Novel Inhibitor of Amyloid β (Aβ) Peptide Aggregation. Journal of Biological Chemistry, 287 (46), 38992 - 39000. doi:10.1074/jbc.M112.348037
DOI: doi:10.1074/jbc.M112.348037
ISSN: 0021-9258
EISSN: 1083-351X
Pages: 287.46: 38992 - 39000
Type of Material: Journal Article
Journal/Proceeding Title: Journal of Biological Chemistry
Version: Final published version. Article is made available in OAR by the publisher's permission or policy.

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