Determination of fibril disaggregation processes in Alzheimer's disease responsible Aß1-40 by means of solid state NMR
Final Report Abstract
Protein misfolding and aggregate formation is linked to a large variety of so far incurable human diseases, including Alzheimer´s disease, Parkinson´s disease, Huntington´s disease and type II diabetes. Fibrils formed by the A peptides (39-43 residues) are the primary component of the plaques found in human brains affected by Alzheimer´s disease. Their presence is directly linked to neurodegenerative processes . In particular, oligomeric A assemblies appear to be the causative species for neurotoxicity . However, the structural basis for toxicity of these structures is not known. In the past, small molecules have been identified that prevent neurotoxicity associated with A peptide deposition. In general, it is not understood which structural changes are induced by these compounds and how they are able to reduce A toxicity. The interactions of 2 different compounds with the A peptide were studied in the present work. Two different mechanisms were characterized by which the neurotoxicity of A can be avoided: EGCG, the main catechin present in green tea induces good structured, non toxic A oligomers. These oligomers were investigated by MAS solid-state NMR spectroscopy. Binding of the EGCG molecule to the HHQKLVFF peptide core were detected, indicating a key role of the disruption of the amyloid aromatic interactions on the destabilization of fibrillar structures. The stabilization of off-pathway oligomers is thus responsible of the reduced neurotoxicity in this case. The orcein related compound O4 on the contrary, accelerates Aβ fibrillogenesis through direct binding to the hydrophobic amino acid residues in Aβ peptides. It stabilizes the self-assembly of seeding-competent, β-sheet-rich protofibrils and fibrils. Strikingly, O4-mediated acceleration of amyloid fibril formation efficiently decreased the concentration of small, toxic Aβ oligomers. These results support the hypothesis that small, diffusible pre-fibrillar amyloid species rather than mature fibrillar aggregates are toxic for mammalian cells. We believe that the characterization of these mechanisms will have a broad impact in the future design of therapeutically effective drugs of the Alzheimer´s disease. The design of new methods of amyloid analysis by solid state NMR, the identification of an asymmetric dimmer as the basic constituent of the A fibrils and the identification of bacterial inclusion bodies as native-like aggregation intermediate states, are also important contributions towards the further understanding of this terrible illness.
Publications
- Journal of Biomolecular NMR (2010) 48 (4), 203-212. Quantification of Protein Backbone Hydrogen-Deuterium Exchange Rates by Solid State NMR Spectroscopy
Lopez del Amo JM, Fink U, Reif B
- Angewandte Chemie International Edition, (2011) 50 (19), 4508-4512. Proton-Detected Solid-State NMR Spectroscopy of Fibrillar and Membrane Proteins
Linser R, Dasari M, Hiller M, Higman V, Fink U, Lopez del Amo JM, Markovic S, Handel L, Kessler B, Schmieder P, Oesterhelt D, Oschkinat H, Reif B
- ChemBioChem (2011) 12 (3), 407-423. Bacterial Inclusion Bodies of Alzheimer´s Disease β-Amiloid Peptides can be Employed to Study Native-Like Aggregation Intermediate States
Dasari M, Espargaro A, Sabate R, Lopez del Amo JM, Fink U, Grelle G, Bieschke J, Ventura S, Reif B
