Format

Send to

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

Differentiating Alzheimer disease-associated aggregates with small molecules.

Author information

1
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
PMCID:
PMC2194600
DOI:
10.1016/j.nbd.2007.07.018
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center