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Aβ40 has a subtle effect on Aβ42 protofibril formation, but to a lesser degree than Aβ42 concentration, in Aβ42/Aβ40
Shana E Terrill-Usery1, Benjamin A Colvin1, Richard E Davenport1
1Department of Chemistry and Biochemistry, Center for Nanoscience, University of Missouri, St. Louis, USA.
Abstract:
Recent findings suggest that the senile plaques in Alzheimer's disease may contain soluble amyloid-β peptide (Aβ) fibril precursors along with insoluble fibrils. These soluble Aβ species, including oligomers and protofibrils, have been well-studied in vitro and are formed via non-covalent self-assembly of Aβ monomers. While both 40- and 42-residue forms of Aβ are observed in the human body, the majority of the Aβ aggregation work has been conducted on Aβ42 or Aβ40 separately, with relatively few investigations of mixtures. In order to study the effect of different combinations of Aβ40 and Aβ42 on protofibril formation, mixtures of either dry solid peptide, or purified Aβ40 and Aβ42 monomer solutions were mixed together and protofibril/monomer distributions were quantified. Increases in the Aβ42/Aβ40 ratio increased protofibril formation but the presence of Aβ40 in the mixed Aβ solutions had a significant negative impact on protofibril formation compared to equivalent solutions of pure Aβ42. Protofibril size was less affected, but β-sheet structure increased with protofibrils formed from higher Aβ42/Aβ40 ratio solutions. Direct measurement of Aβ42/Aβ40 ratios by C-terminal-selective ELISA found very little Aβ40 incorporated into protofibrils. The cumulative data emphasizes the critical importance of Aβ42, yet establishes Aβ40 as a regulator of Aβ42 aggregation.
Insights
Alzheimer's disease amyloid-β peptide (Aβ) plaques contain soluble precursors. Higher ratios of Aβ42 to Aβ40 increase protofibril formation, with Aβ40 regulating Aβ42 aggregation.
Area of Science:
- Neuroscience
- Biochemistry
- Molecular Biology
Background:
- Senile plaques in Alzheimer's disease (AD) may contain soluble amyloid-β peptide (Aβ) fibril precursors, including oligomers and protofibrils.
- These soluble Aβ species are formed via non-covalent self-assembly of Aβ monomers.
- Research has primarily focused on Aβ40 or Aβ42 individually, with limited investigation into their mixtures.
Purpose of the Study:
- To investigate the effect of varying Aβ42/Aβ40 ratios on protofibril formation.
- To quantify protofibril and monomer distributions in mixed Aβ solutions.
- To understand the role of Aβ40 in modulating Aβ42 aggregation.
Main Methods:
- Preparation of mixed Aβ40 and Aβ42 solutions from dry peptide or purified monomers.
- Quantification of protofibril and monomer distributions.
- Measurement of Aβ42/Aβ40 ratios in protofibrils using C-terminal-selective ELISA.
- Assessment of β-sheet secondary structure content.
Main Results:
- Increased Aβ42/Aβ40 ratios promoted protofibril formation.
- Aβ40 significantly inhibited protofibril formation in mixed solutions compared to pure Aβ42.
- Protofibril size was minimally affected, but β-sheet content increased with higher Aβ42/Aβ40 ratios.
- C-terminal-selective ELISA revealed minimal Aβ40 incorporation into protofibrils.
Conclusions:
- Aβ42 is critical for protofibril formation in Alzheimer's disease.
- Aβ40 acts as a regulator of Aβ42 aggregation, significantly impacting protofibril formation.
- Understanding the interplay between Aβ40 and Aβ42 is crucial for elucidating AD pathogenesis.
