Significant Structural Differences between Transient Amyloid-$β$ Oligomers and Less-Toxic Fibrils in Regions Known To Harbor Familial Alzheimer's Mutations. Sarkar, B., Mithu, V. S., Chandra, B., Mandal, A., Chandrakesan, M., Bhowmik, D., Madhu, P. K, & Maiti, S. Angewandte Chemie (International ed. in English), 53(27):6888–6892, July, 2014. ![Significant Structural Differences between Transient Amyloid-$β$ Oligomers and Less-Toxic Fibrils in Regions Known To Harbor Familial Alzheimer's Mutations. [link]](https://bibbase.org/img/filetypes/link.svg "link")
Paper doi abstract bibtex Small oligomers of the amyloid $β$ (A$β$) 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 A$β$40 oligomers that demonstrate a potential sign of toxicity, namely, an enhanced affinity for cell membranes, were thus probed. The two hydrophobic regions (residues 10-21 and 30-40) have already attained the conformation that is observed in the fibrils. However, the turn region (residues 22-29) and the N-terminal tail (residues 1-9) are strikingly different. Notably, ten of eleven known A$β$ 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.
@article{Sarkar2014a,
title = {Significant {Structural} {Differences} between {Transient} {Amyloid}-\$β\$ {Oligomers} and {Less}-{Toxic} {Fibrils} in {Regions} {Known} {To} {Harbor} {Familial} {Alzheimer}'s {Mutations}.},
volume = {53},
issn = {1521-3773},
url = {http://www.ncbi.nlm.nih.gov/pubmed/24756858},
doi = {10.1002/anie.201402636},
abstract = {Small oligomers of the amyloid \$β\$ (A\$β\$) 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 A\$β\$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 A\$β\$ 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.},
number = {27},
journal = {Angewandte Chemie (International ed. in English)},
author = {Sarkar, Bidyut and Mithu, Venus Singh and Chandra, Bappaditya and Mandal, Arghya and Chandrakesan, Muralidharan and Bhowmik, Debanjan and Madhu, Perunthiruthy K and Maiti, Sudipta},
month = jul,
year = {2014},
pmid = {24756858},
pages = {6888--6892},
}
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A method for addressing such problems has been developed by combining rapid fluorescence techniques with slower two-dimensional solid-state NMR methods. The smallest A$β$40 oligomers that demonstrate a potential sign of toxicity, namely, an enhanced affinity for cell membranes, were thus probed. The two hydrophobic regions (residues 10-21 and 30-40) have already attained the conformation that is observed in the fibrils. However, the turn region (residues 22-29) and the N-terminal tail (residues 1-9) are strikingly different. Notably, ten of eleven known A$β$ mutants that are linked to familial AD map to these two regions. 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