Resveratrol selectively remodels soluble oligomers and fibrils of amyloid Abeta into off-pathway conformers.
Misfolded proteins associated with diverse aggregation disorders assemble not only into a single toxic conformer but rather into a suite of aggregated conformers with unique biochemical properties and toxicities. To what extent small molecules can target and neutralize specific aggregated conformers is poorly understood. Therefore, we have investigated the capacity of resveratrol to recognize and remodel five conformers (monomers, soluble oligomers, non-toxic oligomers, fibrillar intermediates, and amyloid fibrils) of the Abeta1-42 peptide associated with Alzheimer disease. We find that resveratrol selectively remodels three of these conformers (soluble oligomers, fibrillar intermediates, and amyloid fibrils) into an alternative aggregated species that is non-toxic, high molecular weight, and unstructured. Surprisingly, resveratrol does not remodel non-toxic oligomers or accelerate Abeta monomer aggregation despite that both conformers possess random coil secondary structures indistinguishable from soluble oligomers and significantly different from their beta-sheet rich, fibrillar counterparts. We expect that resveratrol and other small molecules with similar conformational specificity will aid in illuminating the conformational epitopes responsible for Abeta-mediated toxicity.
Ladiwala
Ali Reza A
AR
Department of Chemical and Biological Engineering, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180, USA.
Lin
Jason C
JC
Bale
Shyam Sundhar
SS
Marcelino-Cruz
Anna Marie
AM
Bhattacharya
Moumita
M
Dordick
Jonathan S
JS
Tessier
Peter M
PM
D000313:Adrenal Medulla / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D052160:Benzothiazoles; D000939:Epitopes / Q000737:chemistry; D018625:Microscopy, Atomic Force; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D051381:Rats; D000077185:Resveratrol; D016622:Silver Staining; D013267:Stilbenes / Q000494:pharmacology*; D013844:Thiazoles / Q000737:chemistry
D016229:Amyloid beta-Peptides; D000975:Antioxidants; D052160:Benzothiazoles; D000939:Epitopes; D010455:Peptides; D013267:Stilbenes; D013844:Thiazoles; C009462:thioflavin T; D000077185:Resveratrol