Differentiating Alzheimer disease-associated aggregates with small molecules.
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.
Honson
Nicolette S
NS
Center for Molecular Neurobiology, The Ohio State University, 1060 Carmack Rd, Columbus, OH 43210, USA.
Johnson
Ronald L
RL
Huang
Wenwei
W
Inglese
James
J
Austin
Christopher P
CP
Kuret
Jeff
J
D000544:Alzheimer Disease / Q000175:diagnosis* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D052160:Benzothiazoles; D004305:Dose-Response Relationship, Drug; D005456:Fluorescent Dyes / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D013058:Mass Spectrometry / Q000379:methods; D016874:Neurofibrillary Tangles / Q000378:metabolism*; D019151:Peptide Library; D058225:Plaque, Amyloid / Q000378:metabolism*; D013843:Thiazines / Q000737:chemistry / Q000493:pharmacokinetics; D013844:Thiazoles / Q000737:chemistry / Q000493:pharmacokinetics; D051844:alpha-Synuclein / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D005456:Fluorescent Dyes; D019151:Peptide Library; D013843:Thiazines; D013844:Thiazoles; D051844:alpha-Synuclein; D016875:tau Proteins; C009462:thioflavin T