Amyloid‐β40 E22K fibril in familial Alzheimer's disease is more thermostable and susceptible to seeding

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 o...

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Bibliographic Details
Published in:IUBMB life 2022-08, Vol.74 (8), p.739-747
Main Authors: Lee, Ming‐Che, Liao, Yi‐Hung, Chen, Shih‐Hui, Chen, Yun‐Ru
Format: Article
Language:English
Subjects:
Aged
Alzheimer Disease - genetics
Alzheimer's disease
Amyloid - chemistry
Amyloid - genetics
Amyloid beta-Peptides - genetics
amyloid‐β
Circular dichroism
familial mutation
Fibrils
Fourier transforms
High temperature
Humans
Mutation
Neurodegenerative Diseases
Peptide Fragments - chemistry
Peptide Fragments - genetics
Protein seeding
Protein structure
Secondary structure
seeding
Seeds
Senile plaques
Spectroscopy
stability
Thermal stability
Transmission electron microscopy
β-Amyloid
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Summary: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.
ISSN:1521-6543
1521-6551
DOI:10.1002/iub.2570