Abstract
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.
Highlights
A intriguing aspect of protein misfolding is that a single polypeptide chain can adopt multiple aggregated conformations with unique biological activities [13]
Using a second conformation-specific antibody (OC) that selectively recognizes fibrillar intermediates and fibrils [47], we found that OC-positive conformers did not assemble either before or after formation of soluble prefibrillar oligomers (Fig. 1A)
We confirmed that A conformers formed on days 4 and 5 were off-pathway conformers that possess similar morphologies to soluble oligomers, yet they were SDS-resistant, Thioflavin T (ThT)-negative, and non-toxic
Summary
A intriguing aspect of protein misfolding is that a single polypeptide chain can adopt multiple aggregated conformations with unique biological activities [13]. Their findings suggest that different small molecules can selectively inhibit formation of two unique aggregated conformers (soluble prefibrillar oligomers and amyloid fibrils). We have formed four well characterized 〈 conformations (soluble oligomers, non-toxic oligomers, fibrillar intermediates, and amyloid fibrils) in addition to monomeric 〈.
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