The dye, a compound called orcein, and the related substance O4, bind preferentially to small amyloid aggregates that are considered to be toxic and cause neuronal dysfunction and memory impairment in Alzheimer’s disease. O4 binding to small aggregates promotes their conversion into large, mature plaques which researchers from the Max Delbrück Center (MDC) and the Charité – Universitätsmedizin Berlin in Germany assume to be largely non-toxic for neuronal cells (Nature Chemical Biology, doi: http://dx.doi.org/10.1038/NCHEMBIO.719)*.
Further research with animal models is needed to determine whether this new approach by Dr. Jan Bieschke (MDC), Dr. Martin Herbst (Charité) and Professor Erich Wanker (MDC) will be useful for therapy development.
Protein misfolding is considered to be the cause of Alzheimer’s, Parkinson’s and also Huntington’s disease. In a multistep process, proteins misfold and accumulate into large extra- or intracellular plaques. Researchers assume that small misfolded protein aggregates that are precursors of mature plaques are toxic for nerve cells and are the reason why they are eventually destroyed.
“This is a new mechanism,” Professor Wanker explained. “Up to now it has been considered to be very difficult to stop the formation of small toxic protein assemblies. If our hypothesis is correct that the small aggregates, which are precursors of plaques, indeed cause neuronal death, with O4 we would have a new mechanism to attack the disease.”
The synthetic dye methylene blue is currently being tested in clinical trials. This dye also seems to stimulate the formation of large plaques in a way similar to O4. Other therapeutic approaches tested in clinical trials which aim at eliminating small precursor aggregates have so far not led to a significant improvement of disease symptoms.
However, it still remains to be seen whether the blue dye O4 can also be effective against small amounts of misfolded proteins in the brains of Alzheimer’s patients and whether the accelerated formation of larger plaques can indeed reduce the signs and symptoms of Alzheimer’s disease in humans. Further studies will be necessary to address the question whether the accelerated formation of large plaques can be a therapeutic approach. “We hope that our findings will stimulate research activities in this direction, especially in drug discovery,” Professor Wanker said.*Small-molecule conversion of toxic oligomers to nontoxic b-sheet–rich amyloid fibrils
Jan Bieschke1,12, Martin Herbst1,2,12, Thomas Wiglenda1, Ralf PFriedrich1, Annett Boeddrich1, Franziska Schiele1, Daniela Kleckers1, Juan Miguel Lopez del Amo3, Björn Grüning4, Qinwen Wang5,11, Michael RSchmidt1, Rudi Lurz6, Roger Anwyl5, Sigrid Schnoegl1, Marcus Fändrich7, Ronald F Frank8, Bernd Reif3,9, Stefan Günther4, Dominic M Walsh10 & Erich EWanker1
1Neuroproteomics, Max Delbrück Center for Molecular Medicine, Berlin, Germany. 2Department of Neurology, Charité-Universitätsmedizin Berlin, Germany. 3Leibniz Institute for Molecular Pharmacology, Berlin, Germany. 4Institute for Pharmaceutical Sciences, University of Freiburg, Germany. 5Department of Physiology, School of Medicine, Trinity College, Dublin, Republic of Ireland, 6Max Planck Institute for Molecular Genetics, Berlin, Germany. 7Max Planck Research Unit for Enzymology of Protein Folding, Halle (Saale), Germany. 8Department of Chemistry, Helmholtz Center for Infection Research, Braunschweig, Germany. 9Technical University Munich, Munich, Germany. 10Laboratory for Neurodegenerative Research, The Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Republic of Ireland. 11Present address: Department of Physiology and Pharmacology, Medical School, Ningbo University, Ningbo, China. 12These authors contributed equally to this work.Barbara Bachtler
Barbara Bachtler | Max-Delbrück-Centrum
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