INANO scientists publish structure of peptide associated with Alzheimer’s disease

Scientists at iNANO and the Department of Chemistry determine structure of an Aβ peptide in the oligomeric state with implications for the understanding of Alzheimer’s disease.

2014.09.30 | Morten Bjerring

Example of a 2D solid-state NMR spectrum of the AβCC oligomer (left), which supplemented with data from several other spectra leads to determination of the structure of the peptide in the oligomeric state – seen from two different perspectives (right). Click to see the full figure.

Alzheimer’s disease is a severe and frequently occurring disorder which leads to impaired brain function for mostly elderly people, and roughly 35 million persons worldwide are affected by the disease. The origin of Alzheimer’s disease is still not established, however, it is well-known that plaques of the Aβ peptide in its fibrillar form are deposited in the brains of people suffering from the disorder. The fibril is the end product of the peptide which undergoes a cascade of events during the progress of the disease, and it is debated which form is the toxic one.

Oligomers and protofibrils as the toxic species

However, much evidence points at the oligomeric and protofibrillar form, and it is highly relevant to investigate these states. Until now investigations of the Aβ oligomers have been complicated by the instability of these, making long-term experiments impossible. Therefore, a research group in Uppsala, Sweden has engineered a Aβ variant, called AβCC, which has the same properties as the wild-type peptide, but the AβCC variant is not converted to mature fibrils because of a chemical binding between two cysteins in the mutated peptide.

Structure determination of the peptide

In collaboration with the Swedish research group in Uppsala, researchers at iNANO and Department of Chemistry at Aarhus University have solved the structure of the AβCC peptide in the highly important oligomeric state. The primary tool applied for in this work is solid-state NMR spectroscopy where a number of internuclear contacts were identified from several multidimensional NMR spectra. From these contacts it was possible to calculate the structure of the single peptide in the oligomer, and also the tertiary organization of the individual peptides in the oligomer.

Important step towards deeper understanding

The determination of the AβCC oligomer structure is an important step towards a deeper understanding of the molecular process leading eventually to Alzheimer’s disease. This understanding may in the next step lead to development of marker molecules for early-stage diagnosis of the disease – a challenge taken up by several researchers at Aarhus University. In a longer perspective the aim is to develop drugs that can inhibit or slow down the progress of Alzheimer’s disease, and in that work solid-state NMR is also expected to be an invaluable tool.

 

Read the full paper here:

onlinelibrary.wiley.com/doi/10.1002/anie.201406357/pdf

For further information, please contact:

Morten Bjerring, PhD

iNANO and Department of Chemistry

bjerring@chem.au.dk

or Dean Niels Chr. Nielsen

iNANO and Department of Chemistry

ncn@inano.au.dk

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