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Honson, Nicolette S., Johnson, Ronald L., Huang, Wenwei,
Inglese, James, Austin, Christopher P., Kuret, Jeff, Differentiating Alzheimer
Disease-Associated Aggregates with Small Molecules, Neurobiology of Disease (2007), doi:
10.1016/j.nbd.2007.07.018

Alzheimer disease is diagnosed postmortem by the density and spatial distribution of β-amyloid
plaques and tau-bearing neurofibrillary tangles. The major protein component of each lesion
adopts cross-β-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-β-sheet forming protein, α-synuclein. To
determine the feasibility of distinguishing tau aggregates from β-amyloid and α-synuclein
aggregates with small molecule probes, a library containing 71,975 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.

Source & Full text: Genome.gov Neurobiology of Disease

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