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Significant Structural Differences between Transient Amyloid‐β Oligomers and Less‐Toxic Fibrils in Regions Known To Harbor Familial Alzheimer′s Mutations
Author(s) -
Sarkar Bidyut,
Mithu Venus Singh,
Chandra Bappaditya,
Mandal Arghya,
Chandrakesan Muralidharan,
Bhowmik Debanjan,
Madhu Perunthiruthy K.,
Maiti Sudipta
Publication year - 2014
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201402636
Subject(s) - fibril , chemistry , monomer , biophysics , amyloid (mycology) , peptide , mutant , fluorescence , biochemistry , biology , gene , polymer , inorganic chemistry , physics , organic chemistry , quantum mechanics
Small oligomers of the amyloid β (Aβ) peptide, rather than the monomers or the fibrils, are suspected to initiate Alzheimer′s disease (AD). However, their low concentration and transient nature under physiological conditions have made structural investigations difficult. A method for addressing such problems has been developed by combining rapid fluorescence techniques with slower two‐dimensional solid‐state NMR methods. The smallest Aβ 40 oligomers that demonstrate a potential sign of toxicity, namely, an enhanced affinity for cell membranes, were thus probed. The two hydrophobic regions (residues 10–21 and 30–40) have already attained the conformation that is observed in the fibrils. However, the turn region (residues 22–29) and the N‐terminal tail (residues 1–9) are strikingly different. Notably, ten of eleven known Aβ mutants that are linked to familial AD map to these two regions. Our results provide potential structural cues for AD therapeutics and also suggest a general method for determining transient protein structures.