Strukturelle und funktionelle Charakterisierung von ß-Amyloid Aggregations-Intermediaten
Final Report Abstract
The project was aiming at an integrated analysis of aggregates formed by the Alzheimer's disease β-amyloid (Aβ) peptide induced by small molecules, involving a detailed biophysical characterization and a MAS solid-state NMR study. Aβ oligomers which are transiently populated in the due course of aggregation. They are believed to be the most toxic species on the amyloid pathway. Incubation of small molecules can trap off-pathway oligomers and can make these aggregates accessible for a NMR structural characterization. We found that Aβ oligomeric structures induced by small molecules are structurally homogeneous and amenable for a structural characterization using MAS solid-state NMR. After addition of the polyphenol epigallocatechin-gallate (EGCG), Aβ adopts β-sheet structure involving the residues Gly29-Val36. A more detailed structural characterization of EGCG induced Aβ oligomeric aggregates is currently in progress in our laboratory. We furthermore found that drugs, such as the Orcein derivate O4 that stabilize the fibrillar state of Aβ, depopulate the oligomeric state and rescue amyloid toxicity. O4 binds to Aβ along the fibril axis and prevent dissociation of monomers. Formation of β-sheet structures correlates with toxicity and with uptake of Aβ into neurons. In contrast, mature fibrils are unable to enter the cell.
Publications
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(2011) Black tea theaflavins inhibit formation of toxic amyloid-β and α-synuclein fibrils, Biochemistry 50, 10624-36
Grelle G, Otto A, Lorenz M, Frank RF, Wanker EE, Bieschke J
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(2011). Bacterial Inclusion Bodies of the Alzheimer Disease beta-Amyloid Peptides can be employed to study Native like Aggregation Intermediate States. ChemBioChem 12, 407 – 423
Dasari, M., Espargaro, A., Sabate, R., Lopez del Amo, J.M., Fink, U., Grelle, G., Bieschke, J., Ventura, S., and Reif, B.
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(2012). Small-molecule conversion of toxic oligomers to nontoxic ß-sheet rich amyloid fibrils. Nature Chem Biol 8, 93-101
Bieschke, J., Herbst, M., Wiglenda, T., Friedrich, R., Boeddrich, A., Schiele, F., Kleckers, D., Lopez del Amo, J.-M., Gruening, B., Wang, Q., Schmidt, M., Lurz, R., Anwyl, R., Schnoegl, S., Fändrich, M., Frank, R., Reif, B., Guenther, S., Walsh, D., and Wanker, E.E.
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(2012). Structural Properties of EGCG induced, non-toxic Alzheimer's disease Aβ oligomers J Mol Biol 421, 517-524
Lopez del Amo, J.-M., Dasari, M., Fink, U., Grelle, G., Wanker, E.E., Bieschke, J., and Reif, B.
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(2012). The basic subunit in Alzheimer's disease beta-amyloid fibrils can be an asymmetric dimer. Angewandte Chemie Int Edt Engl 51, 6136 –6139
Lopez del Amo, J.M., Schmidt, M., Fink, U., Dasari, M., Fändrich, M., and Reif, B.
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(2015) The Effect of (-)-Epigallo-catechin-(3)-gallate on Amyloidogenic Proteins Suggests a Common Mechanism Adv Exp Med Biol. 2015;863:139-61
Andrich K., Bieschke J.
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(2015). Structural mechanism of the interaction of Alzheimer's disease Aβ fibrils with the NSAID sulindac sulfide. J Biol Chem 290, 28737-28745
Prade, E., Bittner, H.J., Sarkar, R., Lopez del Amo, J.M., Althoff-Ospelt, G., Multhaup, G., Hildebrand, P.W., and Reif, B.
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(2015). The green tea polyphenol (-)-epigallocatechin gallate prevents the aggregation of tau protein into toxic oligomers at substoichiometric ratios. FEBS Lett. 589, 77-83
Wobst H.J., Sharma A., Diamond M.I., Wanker E.E., Bieschke J.
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Amyloid–ß1–42 aggregation initiates its cellular uptake and cytotoxicity, J. Biol. Chem, 2016 Sep 9;291(37):19590-606
Jin, S. Illes-Toth, E, Haralampiev, I., Kedia, N., Herrmann, A., Wanker E.E., Bieschke, J.
