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Alzheimer’s amyloid-β A2T variant and its N-terminal peptides inhibit amyloid-β fibrillization and rescue the induced cytotoxicity
- Source :
- PLoS ONE, PLoS ONE, Vol 12, Iss 3, p e0174561 (2017)
- Publication Year :
- 2017
- Publisher :
- Public Library of Science, 2017.
-
Abstract
- Alzheimer's disease (AD) is the most common dementia affecting tens of million people worldwide. The primary neuropathological hallmark in AD is amyloid plaques composed of amyloid-β peptide (Aβ). Several familial mutations found in Aβ sequence result in early onset of AD. Previous studies showed that the mutations located at N-terminus of Aβ, such as the English (H6R) and Tottori (D7N) mutations, promote fibril formation and increase cytotoxicity. However, A2T mutant located at the very N-terminus of Aβ shows low-prevalence incidence of AD, whereas, another mutant A2V causes early onset of AD. To understand the molecular mechanism of the distinct effect and develop new potential therapeutic strategy, here, we examined the effect of full-length and N-terminal A2V/T variants to wild type (WT) Aβ40 by fibrillization assays and NMR studies. We found that full-length and N-terminal A2V accelerated WT fibrillization and induced large chemical shifts on the N-terminus of WT Aβ, whereas, full-length and N-terminal A2T retarded the fibrillization. We further examined the inhibition effect of various N-terminal fragments (NTFs) of A2T to WT Aβ. The A2T NTFs ranging from residue 1 to residue 7 to 10, but not 1 to 6 or shorter, are capable to retard WT Aβ fibrillization and rescue cytotoxicity. The results suggest that in the presence of full-length or specific N-terminal A2T can retard Aβ aggregation and the A2T NTFs can mitigate its toxicity. Our results provide a novel targeting site for future therapeutic development of AD.
- Subjects :
- 0301 basic medicine
Magnetic Resonance Spectroscopy
Cytotoxicity
Mutant
lcsh:Medicine
Peptide
Toxicology
Pathology and Laboratory Medicine
Spectrum analysis techniques
Polyacrylamide Gel Electrophoresis
Neuroblastoma
Spectroscopy, Fourier Transform Infrared
Medicine and Health Sciences
Enzyme assays
Blastomas
Colorimetric assays
lcsh:Science
Bioassays and physiological analysis
Gel Electrophoresis
chemistry.chemical_classification
Multidisciplinary
Cytotoxicity Assay
MTT assay
Chemistry
Circular Dichroism
Neurodegenerative Diseases
Native Polyacrylamide Gel Electrophoresis
Neurology
Oncology
Physical Sciences
Alzheimer's disease
Hydrophobic and Hydrophilic Interactions
Research Article
Materials by Structure
Cell Survival
Materials Science
Research and Analysis Methods
03 medical and health sciences
Electrophoretic Techniques
NMR spectroscopy
Microscopy, Electron, Transmission
Alzheimer Disease
Cell Line, Tumor
Mental Health and Psychiatry
medicine
Humans
Amyloid beta-Peptides
lcsh:R
Wild type
Biology and Life Sciences
Cancers and Neoplasms
medicine.disease
Molecular biology
030104 developmental biology
Cell culture
Oligomers
Biochemical analysis
lcsh:Q
Dementia
Subjects
Details
- Language :
- English
- ISSN :
- 19326203
- Volume :
- 12
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....7ca823742289e5ffe341d47dff6a408b