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Alzheimer fibrils at atomic resolution

August 04, 2016

FRANKFURT. Elongated fibres (fibrils) of the beta-amyloid protein form the typical senile plaques present in the brains of patients with Alzheimer's disease. A European research team and a team from the United States (Massachussetts Institute of Technology in cooperation with Lund University) have simultaneously succeeded in elucidating the structure of the most disease-relevant beta-amyloid peptide 1-42 fibrils at atomic resolution. This simplifies the targeted search for drugs to treat Alzheimer's dementia.

Alzheimer's disease is responsible for at least 60 percent of dementia cases worldwide. It causes enormous human suffering and high costs. A cure or causal therapy are not yet available. A reason for this is that the exact course of the illness in the brain at a molecular level has not yet been adequately clarified.

It is known that the beta-amyloid peptide plays a crucial role. This peptide, 39 to 42 amino acids long, is toxic to nerve cells and is able to form elongated fibrils. Beta-amyloid peptide 1-42 and beta-amyloid peptide 1-40 are the two main forms that appear in senile plaques. We do not know why these lead to the decay of nerve cells in the brain, but this question is very interesting for the development of medications to treat Alzheimer's disease.

In a joint project between the Swiss Federal Institute of Technology in Zurich, the University of Lyon, and the Goethe University in Frankfurt am Main, in cooperation with colleagues at the University of Irvine and the Brookhaven National Laboratory, researchers have succeeded in determining the structure of a beta-amyloid peptide 1-42 fibril at an atomic resolution. This fibril presents the greatest danger in this disease. The researchers built on earlier research on the structure of beta-amyloid monomers done at the University of Chicago. Further immunological examinations show that the investigated form of the fibrils is especially relevant to the illness.

Protein fibrils are visible in electron microscope images (Fig. 1), but it is very difficult to go to an atomic level of detail. The standard methods used in structural biology to achieve this assume that the macromolecule is present as a single crystal or in the form of individual molecules that are dissolved in water. However, fibrils are elongated structures that adhere to each other and neither form crystals, nor can be dissolved in water.

Only solid-state nuclear magnetic resonance spectroscopy (solid-state NMR) is capable of offering a view at the atomic level in this case. New developments in methods made it possible to measure a network of distances between the atoms in the protein molecules that make up a fibril (Fig. 2). Extensive calculations enabled the atomic structure of the fibril to be reconstructed from these measurements.

The main part of the beta-amyloid 1-42 peptide is shaped like a double horseshoe (Fig. 3). Pairs of identical molecules form layers, which are stacked onto each other to form a long fibril. Numerous hydrogen bonds parallel to the long axis lend the fibrils their high stability.

"The structure differs fundamentally from earlier model studies, for which barely any experimental measurement data was available." explains Prof Peter Güntert, professor of computational structural biology at Goethe University.

The publications released by the two teams, which confirm each other, have caused excitement in expert circles, as they enable a targeted, structure-based search for medicines that will attack the beta-amyloid fibrils. The researchers hope that this scourge of old age, first described 110 years ago by the Frankfurt-based physician Alois Alzheimer, will finally be defeated over the next one or two decades.
-end-
Publications:

Wälti, M. A., Ravotti, F., Arai, H., Glabe, C., Wall, J., Böckmann, A., Güntert, P., Meier, B. H. & Riek, R. Atomic-resolution structure of a disease-relevant Aβ(1-42) amyloid fibril. Proceedings of the National Academy of Sciences of the United States of America, DOI 10.1073/pnas.1600749113.

http://dx.doi.org/10.1073/pnas.1600749113

Colvin, M. T., Silvers, R., Ni, Q. Z., Can, T. V., Sergeyev, I., Rosay, M., Donovan, K. J., Michael, B., Wall, J., Linse, S. & Griffin, R. G. Atomic resolution structure of monomorphic Aβ42 amyloid fibrils. Journal of the American Chemical Society, DOI 10.1021/jacs.6b05129.

Xiao, Y., Ma, B., McElheny, D., Parthasarathy, S., Long, F., Hoshi, M., Nussinov, R. & Ishii, Y. Aβ(1-42) fibril structure illuminates self-recognition and replication of amyloid in Alzheimer's disease. Nature Structural & Molecular Biology 22, 499-505 (2015).

Images are available for download here (insert link)

Captions:

Fig. 1: Electron microscope image of Alzheimer fibrils

Fig. 2: Network of distance measurements in the protein molecule

Fig. 3: Structure of the amyloid-beta 1-42 fibrils

Information:

Prof. Peter Güntert
Institut of Biophysical Chemistry
Campus Riedberg
Tel.: (069)-798-29621
guentert@em.uni-frankfurt.de.

Goethe University is a research-oriented university in the European financial centre Frankfurt The university was founded in 1914 through private funding, primarily from Jewish sponsors, and has since produced pioneering achievements in the areas of social sciences, sociology and economics, medicine, quantum physics, brain research, and labour law. It gained a unique level of autonomy on 1 January 2008 by returning to its historic roots as a "foundation university". Today, it is among the top ten in external funding and among the top three largest universities in Germany, with three clusters of excellence in medicine, life sciences and the humanities. Together with the Technical University of Darmstadt and the University of Mainz, it acts as a partner of the inter-state strategic Rhine-Main University Alliance.

Current news about science, teaching, and society in GOETHE-UNI online.

Goethe University Frankfurt

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