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    Neurobiol Dis. 2007 Dec;28(3):251-60. Epub 2007 Jul 28.

    Differentiating Alzheimer disease-associated aggregates with small molecules.

    Source

    Center for Molecular Neurobiology, The Ohio State University, 1060 Carmack Rd, Columbus, OH 43210, USA.

    Abstract

    Alzheimer disease is diagnosed postmortem by the density and spatial distribution of beta-amyloid plaques and tau-bearing neurofibrillary tangles. The major protein component of each lesion adopts cross-beta-sheet conformation capable of binding small molecules with submicromolar affinity. In many cases, however, Alzheimer pathology overlaps with Lewy body disease, characterized by the accumulation of a third cross-beta-sheet forming protein, alpha-synuclein. To determine the feasibility of distinguishing tau aggregates from beta-amyloid and alpha-synuclein aggregates with small molecule probes, a library containing 72,455 small molecules was screened for antagonists of tau-aggregate-mediated changes in Thioflavin S fluorescence, followed by secondary screens to distinguish the relative affinity for each substrate protein. Results showed that >10-fold binding selectivity among substrates could be achieved, with molecules selective for tau aggregates containing at least three aromatic or rigid moieties connected by two rotatable bonds.

    PMID:
    17761424
    [PubMed - indexed for MEDLINE]
    PMCID:
    PMC2194600
    Free PMC Article

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