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The Department of Biomedicine

BBB Seminar: Astrid Gräslund

The amyloid β peptide involved in Alzheimer´s disease: molecular interactions and secondary structure conversions

Astrid Gräslund
Department of Biochemistry and Biophysics, Arrhenius Laboratories, Stockholm University, Sweden

The amyloid β (Aβ) peptide consists of 39-43 residues and is the major component of neuritic plaques in the brain from patients suffering from Alzheimer's disease. In aqueous solution the Aβ peptide aggregates and forms beta-sheet structures, finally forming solid fibrils. We study the structure conversions and aggregation properties of the Aβ(1-40) peptide using high resolution NMR spectroscopy. At low concentrations, low temperatures and low ionic conditions in an aqueous solution, Aβ(1-40) is monomeric. Although the peptide displays only weak propensities towards secondary structure, CD and NMR can be used to characterize these propensities in different segments of the peptide, also after adding metal ions like zinc or copper [1-3]. The metal ions bind to ligands in the N-terminus of the peptide, and induce increased order in the N-terminus.

By gradually adding the detergent lithium dodecyl sulphate (LiDS) or SDS to a dilute aqueous solution of Aβ(1-40), secondary structure conversions of Aβ(1-40) can be observed [4]. An initial transition after adding small amounts of LiDS involves conversion of the weakly structured peptide to b-sheet structure, concomitant with formation of large aggregates. This structural transition may mimic the behavior of the Aβ peptide, forming oligomeric structures at a crowded membrane surface. At concentrations close to the detergent CMC or above, a second transition makes the peptide rearrange to form a partly a-helical structure, concomitant with disaggregation and formation of normal LiDS micelles which apparently partly dissolve the aggregates. This a-helical structure is similar to that previously observed by NMR at high SDS concentrations. It has two a-helical segments, Aβ(16-24) and (29-35), separated by a flexible hinge, and flexible unstructured N- and C-termini [5].

References:

1. Danielsson, J., Jarvet, J., Damberg, P. and Gräslund, A. The Alzheimer β-peptide shows temperature-dependent transitions between left-handed 31-helix, β-strand and random coil secondary structures. FEBS J. 272 (2005) 3938-3949.

2. Danielsson, J., Andersson, A., Jarvet, J. and Gräslund, A. 15N relaxation study of the amyloid β peptide: structural propensities and persistence length. Magn. Res. Chem. 44 (2006) S114-S121.

3. Danielsson, J., Pierattelli, R., Banci, L. and Gräslund, A. High resolution NMR studies of the zinc-binding site of the Alzheimer´s amyloid β-peptide. FEBS J. 274 (2007) 46-59.

4. Wahlström, A., Hugonin, L., Peralvarez-Marin, A., Jarvet, J. and Gräslund, A. Secondary structure conversions of Alzheimer´s Aβ(1-40) peptide induced by membrane-mimicking detergents. FEBS J. 275 (2008) 5117-5128.

5. Jarvet, J., Danielsson, J., Damberg, P., Oleszczuk, M. and Gräslund, A. Positioning of Alzheimer Aβ(1-40) peptide in SDS micelles using NMR and paramagnetic probes. J. Biomol. NMR 39 (2007) 63-72.

Host: Aurora Martinez (aurora.martinez@biomed.uib.no), Department of Biomedicine