Researchers have probed the short-lived and toxic amyloid beta oligomers, thought to be responsible for Alzheimer’s disease, and identified two regions as the hotbeds of all disease-causing mutations. They combined two techniques to precisely map the structure of these oligomers -- fast fluorescence spectroscopy and slower solid-state nuclear magntic resonance (NMR)1.
The researchers say their findings could provide potential structural cues for Alzheimer’s disease therapeutics and also suggest a general method for determining transient protein structures.
“The key culprits behind many incurable human diseases, such as Alzheimer’s and Parkinson’s, are not some external infectious agents, but our own proteins,” says one of the researchers Sudipta Maiti.
These proteins are normally benign but under certain conditions, they somehow start sticking together to form small toxic particles or oligomers, and eventually less toxic larger particles. Designing drugs for them would be easier if scientists could understand their structure, but their fleeting nature puts that beyond the reach of most techniques.
With the technique that combines fast fluorescence spectroscopy with slower solid-state NMR, the researchers have been able to decipher the structure of amyloid beta oligomers, which last for only a few minutes after their preparation.
“We found that their structure differs from the less-toxic mature fibrils only in two specific regions. Interestingly, 10 of 11 known disease-causing mutations occur in these two particular regions,” Maiti adds.
The results provide a structural basis to the differences between toxic and nontoxic conformations of amyloid beta and also to the familial forms of Alzheimer’s disease. They also present atomic-level structural markers for developing potential Alzheimer therapeutics.
The authors of this work are from: Department of Chemical Sciences, Tata Institute of Fundamental Research, Mumbai; Department of Biochemistry, Seth G. S. Medical College and KEM Hospital, Mumbai and TIFR Centre for Interdisciplinary Sciences, Hyderabad.
1. Sarkar, B. et al. Significant structural differences between transient amyloid-β oligomers and less-toxic fibrils in regions known to harbor familial Alzheimer′s mutations. Angew. Chem. Int. Edit. 53, 6888–6892 (2014) doi: 10.1002/anie.201402636