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Solution structures of micelle-bound amyloid beta-(1-40) and beta-(1-42) peptides of Alzheimer's disease
1Department of Chemistry, Case Western Reserve University, Cleveland, OH, 44106, USA.
Abstract:
The amyloid beta-peptide is the major protein constituent of neuritic plaques in Alzheimer's disease. The beta-peptide varies slightly in length and exists in two predominant forms: (1) the shorter, 40 residue beta-(1-40), found mainly in cerebrovascular amyloid; and (2) the longer, 42 residue beta-(1-42), which is the major component in amyloid plaque core deposits. We report here that the sodium dodecyl sulphate (SDS) micelle, a membrane-mimicking system for biophysical studies, prevents aggregation of the beta-(1-40) and the beta-(1-42) into the neurotoxic amyloid-like, beta-pleated sheet structure, and instead encourages folding into predominantly alpha-helical structures at pH 7.2. Analysis of the nuclear Overhauser enhancement (NOE) and the alphaH NMR chemical shift data revealed no significant structural differences between the beta-(1-40) and the beta-(1-42). The NMR-derived, three-dimensional structure of the beta-(1-42) consists of an extended chain (Asp1-Gly9), two alpha-helices (Tyr10-Val24 and Lys28-Ala42), and a looped region (Gly25-Ser26-Asn27). The most stable alpha-helical regions reside at Gln15-Val24 and Lys28-Val36. The majority of the amide (NH) temperature coefficients were less than 5, indicative of predominately strong NH backbone bonding. The lack of a persistent region with consistently low NH coefficients, together with the rapid NH exchange rates in deuterated water and spin-labeled studies, suggests that the beta-peptide is located at the lipid-water interface of the micelle and does not become inbedded within the hydrophobic interior. This result has implications for the circulation of membrane-bound beta-peptide in biological fluids, and may also facilitate the design of amyloid inhibitors to prevent an alpha-helix-->beta-sheet conversion in Alzheimer's disease.
Insights
Sodium dodecyl sulphate micelles prevent amyloid beta-peptide aggregation into neurotoxic structures. Instead, they promote alpha-helical folding, offering insights for Alzheimer's disease inhibitor design.
Area of Science:
- Biochemistry
- Neuroscience
- Structural Biology
Background:
- Amyloid beta-peptide is a key component of Alzheimer's disease plaques.
- Two main forms exist: beta-(1-40) in cerebrovascular amyloid and beta-(1-42) in plaque cores.
- Understanding beta-peptide aggregation is crucial for Alzheimer's research.
Purpose of the Study:
- To investigate the structural behavior of amyloid beta-peptide in a membrane-mimicking environment.
- To determine if sodium dodecyl sulphate (SDS) micelles can prevent the formation of neurotoxic beta-sheet structures.
- To elucidate the three-dimensional structure of beta-(1-42) in the presence of SDS micelles.
Main Methods:
- Nuclear Magnetic Resonance (NMR) spectroscopy, including Nuclear Overhauser Enhancement (NOE) and chemical shift analysis.
- Utilized sodium dodecyl sulphate (SDS) micelles as a membrane-mimicking system.
- Studied both beta-(1-40) and beta-(1-42) peptides.
Main Results:
- SDS micelles prevented the aggregation of beta-(1-40) and beta-(1-42) into beta-pleated sheets.
- Micelles promoted the formation of predominantly alpha-helical structures at pH 7.2.
- NMR revealed a detailed 3D structure for beta-(1-42) with specific alpha-helical regions and a looped segment.
- Beta-peptide was found at the micelle's lipid-water interface, not embedded in the hydrophobic core.
Conclusions:
- SDS micelles offer a protective environment against amyloidogenic aggregation.
- The observed alpha-helical structures may represent a non-toxic conformation of beta-peptide.
- Findings suggest implications for beta-peptide circulation and potential therapeutic strategies for Alzheimer's disease by inhibiting alpha-helix to beta-sheet conversion.