Molecular Stew Analysis Produces World´s First Description of Amyloid Intermediate Structures
Scientists of Freie Universität and Max Planck Society succeed in world´s first structural analysis of aggregates believed to be cause of Alzheimer´s disease
№ 315/2016 from Sep 26, 2016
Scientists of Freie Universität Berlin und the Fritz Haber Institute of the Max Planck Society made a major step forward in analyzing the biochemical causes of Alzheimer´s and Parkinson´s disease. The results of Prof. Kevin Pagel and Dr. Gert von Helden´s work could enable the development of new medications fighting the causes of both diseases. Their research was published in the current issue of Nature Chemistry.
Alzheimer´s disease is the most common form of dementia, predominantly in the age group of 65-85 years. There are currently 48 million known patients with Alzheimer´s disease worldwide. This number is expected to double by 2050.
The causes of neurodegenerative diseases like Parkinson´s and Alzheimer´s disease are not fully understood to this day. In both cases, a biochemical disorder can be observed during the course of the disease, but the exact mechanism is unknown. Water-soluble proteins undergo a spontaneous transition into insoluble amyloid fibrils. In the case of Alzheimer´s disease, protein fragments that the body can normally easily dispose accumulate to abnormal species called amyloid plaques, which are deposited outside the neurons and slowly degenerate the brain.
Recent research showed that these plaques are an effect, but not the cause of Alzheimer´s disease. Instead, scientists focus more and more on the issue of what causes the deadly plaque accumulation and why exactly the harmless water-soluble Jekyll proteins turn into the dangerous, insoluble Hyde fibrils. There is increasing evidence that the disease-causing factor is a toxic intermediate that occurs during the aggregation into fibrils, but analyzing the exact structure of these intermediates was an unresolvable problem, resembling the children´s birthday party game of blind man´s bluff. From the perspective of a researcher, the toxic intermediates are not nicely separated species, but present themselves as parts of a stew with unknown ingredients. The research on pharmaceutically active compounds was, therefore, often more or less trial and error up to now. This problem has now been solved by the research of the scientists of Freie Universität and the Fritz Haber Institute.
For the first time the research groups around assistant professor Dr. Kevin Pagel and Dr. Gert von Helden succeeded in developing a method to exactly analyze and describe the toxic intermediates believed to be triggering the disease on a molecular level. They succeeded in separately analyzing each individual ingredient of the stew and specifically describing their structure. Based on this basic research, other scientists can now start developing specific compounds to neutralize the intermediates causing Alzheimer´s disease.
Kevin Pagel and Gert van Helden achieved this using a trick: they combined two elaborate methods. Each method alone is incapable of solving a part of the problem, but combined they did the trick. The first method is ion-mobility spectrometry, which can best be described as a molecular wind tunnel, which separates the intermediates according to their drag coefficient. This method, however, only provides information about the size and shape, but not the molecular structure producing the drag. To shed light on this problem, however, the scientists additionally used gas-phase-infrared spectroscopy. Using this combination of methods, the researchers discovered specific intermediates that closely resemble the structure of the mature Hyde fibrils that are present in deadly amyloid plaques. With the newly developed method, other researchers can now test new medications to specifically tackle the emergence of Alzheimer´s disease.
Die Alzheimer-Krankheit ist die häufigste Form der Demenz, die meist bei Menschen ab dem Rentenalter bis zum 85. Lebensjahr auftritt. In Deutschland leiden zurzeit etwa 1,3 Millionen Menschen an Demenzerkrankungen, 700.000 davon an der Alzheimer-Krankheit. Bis zum Jahr 2050 wird mit einer Verdoppelung der Fallzahlen gerechnet.
Picture for free usage, provided the photographer is credited: Sven Jungtow (other pictures available)
Prof. Dr. Kevin Pagel (at right) and Dr. Gert von Helden (at left)
- Prof. Dr. Kevin Pagel, Institute of Chemistry and Biochemistry, Freie Universität Berlin, Takustraße 3, 14195 Berlin and Fritz Haber Institute of the Max Planck Society, Division of Molecular Physics, Faradayweg 4–6, 14195 Berlin, Tel.: +49 30 – 838 - 72703 (Freie Universität Berlin)/ +49 30 – 8413 - 5646 (Fritz Haber Institute), Email: firstname.lastname@example.org , Web: www.bcp.fu-berlin.de/chemie/pagel
- Dr. Gert von Helden, Fritz Haber Institute of the Max Planck Society, Division of Molecular Physics, Faradayweg 4-6, 14195 Berlin, Tel.: +49 30-8413 – 5615, Email: email@example.com, Web: http://www.fhi-berlin.mpg.de/mp/helden/
Seo, J.; Hoffmann, W.; Warnke, S.; Huang, X.; Gewinner, S.; Schöllkopf, W.; Bowers, M.T.;von Helden, G.; and Pagel, K.; An Infrared Spectroscopy Approach to Follow β-Sheet Formation in Peptide Amyloid Assemblies, Nature Chemistry 2016,doi: 10.1038/NCHEM.2615