Báo cáo khoa học: Physiochemical characterization of the Alzheimer’s disease-related peptides Ab1–42Arctic and Ab1–42wt

Physiochemical Characterization of the Alzheimer’s Disease-Related Peptides Aβ1–42Arctic and Aβ1–42wt

Authors: Ann-Sofi Johansson, Fredrik Berglind-Dehlin, Göran Karlsson, Katarina Edwards, Pär Gellerfors, Lars Lannfelt

Field: Biochemistry, Physical Chemistry

Document Content: This study investigates the aggregation process of amyloid-beta (Aβ) peptides, specifically Aβ1–42 Arctic and Aβ1–42 wild-type (wt). Alzheimer’s disease is characterized by the formation of amyloid plaques composed of Aβ peptides. The aggregation proceeds through soluble intermediates, including protofibrils, which are believed to be central to the disease pathology. The Arctic mutation (E693G) in the amyloid precursor protein leads to early-onset Alzheimer’s disease and enhances protofibril formation. This research examines the kinetics of Aβ1–42wt and Aβ1–42Arctic aggregation under various physicochemical conditions (concentration, temperature, ionic strength, and pH) using size exclusion chromatography. The findings indicate that the Arctic mutation significantly accelerates both protofibril formation and fibril formation. Furthermore, the study demonstrates that monomer oligomerization and protofibril fibrillization are affected differently by changes in the microenvironment, and the Arctic mutation alters the peptide’s response to these changes.

Detailed Table of Contents:

• Introduction to Alzheimer’s Disease and Amyloid-Beta Aggregation
• Keywords: amyloid-β; Arctic; fibrillization; oligomerization; protofibrils
• Experimental Procedures:
• Aβ Peptides
• Preparation of peptide
• Experimental design (Temperature, Aβ concentration, Ion strength, pH)
• Size Exclusion Chromatography (SEC)
• Data Analysis
• Quantitative Amino Acid Analysis
• ThT fluorescence
• Cryo-Transmission Electron Microscopy (Cryo-TEM)
• Results:
• Aβ1–42Arctic assembles into both protofibrils and fibrils faster than the wild-type monomer
• Aβ1–42wt monomer oligomerization is a more energy-dependent process than protofibril fibrillization
• The effect of Aβ peptide concentration on the aggregation process
• Aβ1–42Arc protofibril fibrillization is more dependent on ionic strength than Aβ1–42wt
• Aβ1–42Arc aggregates rapidly at high pH
• Morphology of protofibrils and fibrils
• The Arctic mutation
• Temperature and activation energies
• Discussion
• Acknowledgements
• References