Alzheimer's disease (AD) is the most prevalent and devastating neurodegenerative disease occurred in the elderly. One of the pathogenic hallmarks is senile plaques composed of amyloid-β (Aβ) fibrils. Single mutations resided in Aβ were found in familial AD (FAD) patients that have early onset of the disease. The molecular details and properties of each FAD Aβ variants are still elusive. Here, we employed collective spectroscopic techniques to examine the properties of various Aβ40 fibrils. We generated fibrils of wild type (WT) and three FAD mutants on residue E22 including E22G, E22K, and E22Q. We monitored fibril formation by thioflavin T (ThT) assay, examined secondary structure by Fourier transform infrared and far-UV circular dichroism spectroscopy, imaged fibril morphology by transmission electron microscopy, and evaluated ThT-binding kinetics. In the thermal experiments, we found E22K fibrils resisted to high temperature and retained significant β-sheet content than the others. E22K fibril seeds after high-temperature treatment still possess the seeding property, whereas WT fibril seeds are disturbed after the treatment. Therefore, in this study we demonstrated the mutation at E22K increases the thermal stability and seeding function of amyloid fibrils.
Keywords: Alzheimer's disease; amyloid-β; familial mutation; fibrils; seeding; stability.
© 2021 International Union of Biochemistry and Molecular Biology.