| 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. |
| Authors | Nicolette S Honson, Ronald L Johnson, Wenwei Huang, James Inglese, Christopher P Austin, Jeff Kuret
(Affiliation: Center for Molecular Neurobiology, The Ohio State University, 1060 Carmack Rd, Columbus, OH 43210, USA.)
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| Journal | Neurobiology of disease
(Neurobiol Dis)
Vol. 28
Issue 3
Pg. 251-60
(Dec 2007)
ISSN: 0969-9961 United States |
| PMID | 17761424
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
|
| Chemical References |
- Amyloid beta-Protein
- Fluorescent Dyes
- Peptide Library
- Thiazines
- Thiazoles
- alpha-Synuclein
- tau Proteins
- thioflavin T
|
| Topics |
- Alzheimer Disease
(diagnosis, metabolism)
- Amyloid beta-Protein
(metabolism)
- Dose-Response Relationship, Drug
- Fluorescent Dyes
(chemistry, diagnostic use, pharmacokinetics)
- Humans
- Mass Spectrometry
(methods)
- Neurofibrillary Tangles
(metabolism)
- Peptide Library
- Senile Plaques
(metabolism)
- Thiazines
(chemistry, diagnostic use, pharmacokinetics)
- Thiazoles
(chemistry, diagnostic use, pharmacokinetics)
- alpha-Synuclein
(metabolism)
- tau Proteins
(metabolism)
|
