Abstract
Small oligomers of Aβ are suspected to initiate Alzheimer's disease (AD). However, their low concentration and transient nature under physiological conditions have thwarted efforts to determine their structure. Using time resolved FRET spectroscopy, we have recently shown that the monomers are relatively unstructured, and the aggregation process starts with the two terminals of the peptide coming closer in the small oligomers (n-mers with n<10)1. Here we develop a method which combines rapid fluorescence techniques with slower two-dimensional solid state NMR, and probe nascent Aβ40 oligomers which demonstrate an enhanced ability to attach to cell membranes compared to the monomers2. We find that the conformation of the two hydrophobic arms (residues 10-22 and 29-40) have already reached the conformation observed in the fibrils. However, the turn region (residues 23 to 28) and the N-terminal tail (residues 1-9) are strikingly different. Notably, majority of the Aβ mutants linked to familial AD map to these two regions, and toxicity modulators such as Zn++ affect the same region3. Our results provide specific structural targets for therapeutic strategies designed to modulate Aβ oligomers.Reference:1. S. Nag, B. Sarkar, M. Chandrakesan, R. Abhyankar, D. Bhowmik, M. Kombrabail, S. Dandekar, E. Lerner, E. Haas and S. Maiti, Physical chemistry chemical physics: PCCP, 2013.2. B. Sarkar, A.K.Das and S.Maiti, Front. Physiol. 2013, 4(84), 1-11.3. V.S.Mithu, B. Sarkar, D Bhowmik, M. Chandrakesan, S. Maiti and P.K.Madhu, Biophysics. J. 2011, 101, 2825.
Published Version
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