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Suppression of Oligomer Formation and Formation of Non-Toxic Fibrils upon Addition of Mirror-Image Aβ42 to the Natural l-Enantiomer
, A.R. Foley, C.J.A. Warner, X. Zhang, M. Rolandi, B. Abrams, J.A. Raskatov
Published in Wiley-VCH Verlag
PMID: 28682473
Volume: 56
Issue: 38
Pages: 11506 - 11510
Racemates often have lower solubility than enantiopure compounds, and the mixing of enantiomers can enhance the aggregation propensity of peptides. Amyloid beta (Aβ) 42 is an aggregation-prone peptide that is believed to play a key role in Alzheimer's disease. Soluble Aβ42 aggregation intermediates (oligomers) have emerged as being particularly neurotoxic. We hypothesized that the addition of mirror-image d-Aβ42 should reduce the concentration of toxic oligomers formed from natural l-Aβ42. We synthesized l- and D-Aβ42 and found their equimolar mixing to lead to accelerated fibril formation. Confocal microscopy with fluorescently labeled analogues of the enantiomers showed their colocalization in racemic fibrils. Owing to the enhanced fibril formation propensity, racemic Aβ42 was less prone to form soluble oligomers. This resulted in the protection of cells from the toxicity of l-Aβ42 at concentrations up to 50 μm. The mixing of Aβ42 enantiomers thus accelerates the formation of non-toxic fibrils. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
About the journal
JournalData powered by TypesetAngewandte Chemie - International Edition
PublisherData powered by TypesetWiley-VCH Verlag