Aberrant protein oligomerization is an important pathogenetic process in vivo. In Alzheimer's disease (AD), the amyloid beta-protein (Abeta) forms neurotoxic oligomers. The predominant in vivo Abeta alloforms, Abeta40 and Abeta42, have distinct oligomerization pathways. Abeta42 monomers oligomerize into pentamer/hexamer units (paranuclei) which self-associate to form larger oligomers. Abeta40 does not form these paranuclei, a fact which may explain the particularly strong linkage of Abeta42 with AD. Here, we sought to determine the structural elements controlling paranucleus formation as a first step toward the development of strategies for treating AD. Because oxidation of Met(35) is associated with altered Abeta assembly, we examined the role of Met(35) in controlling Abeta oligomerization. Oxidation of Met(35) in Abeta42 blocked paranucleus formation and produced oligomers indistinguishable in size and morphology from those produced by Abeta40. Systematic structural alterations of the C(gamma)(35)-substituent group revealed that its electronic nature, rather than its size (van der Waals volume), was the factor controlling oligomerization pathway choice. Preventing assembly of toxic Abeta42 paranuclei through selective oxidation of Met(35) thus represents a potential therapeutic approach for AD.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1021/ja0349296 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Partial Destabilization of Amyloid-β Protofibril by Methionine Photo-Oxidation: A Molecular Dynamic Simulation Study.
ACS Omega
March 2023
Center for Biomedical Engineering, University of New Mexico, Albuquerque, New Mexico 87131, United States.
Selective photosensitized oxidation of amyloid protein aggregates is being investigated as a possible therapeutic strategy for treating Alzheimer's disease (AD). Photo-oxidation has been shown to degrade amyloid-β (Aβ) aggregates and ameliorate aggregate toxicity in vitro and reduce aggregate levels in the brains of AD animal models. To shed light on the mechanism by which photo-oxidation induces fibril destabilization, we carried out an all-atom molecular dynamics (MD) simulation to examine the effect of methionine (Met35) oxidation on the conformation and stability of a β-sheet-rich Aβ protofibril.
View Article and Find Full Text PDFHomocysteine thiolactone and H O induce amino acid modifications and alter the fibrillation propensity of the Aβ peptide.
FEBS Lett
April 2023
Department of Chemistry, Indian Institute of Technology Kharagpur, India.
Of the proteinaceous β-sheet-rich amyloid fibrillar structures, the Aβ peptide, a component of the full-length Aβ involved in Alzheimer's disease, has similar toxicity to the parent peptide. In this study, the effects of homocysteine thiolactone (HCTL) and hydrogen peroxide (H O ) on the conformation and fibrillation propensity of the Aβ peptide were investigated. Both HCTL and H O induced amino acid modifications along with alteration in aggregation propensity.
View Article and Find Full Text PDFProtective Effects against the Development of Alzheimer's Disease in an Animal Model through Active Immunization with Methionine-Sulfoxide Rich Protein Antigen.
Antioxidants (Basel)
April 2022
Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, KS 66045, USA.
The brain during Alzheimer's disease (AD) is under severe oxidative attack by reactive oxygen species that may lead to methionine oxidation. Oxidation of the sole methionine (Met35) of beta-amyloid (A), and possibly methionine residues of other extracellular proteins, may be one of the earliest events contributing to the toxicity of A and other proteins in vivo. In the current study, we immunized transgenic AD (APP/PS1) mice at 4 months of age with a recombinant methionine sulfoxide (MetO)-rich protein from (antigen).
View Article and Find Full Text PDFA mass spectrometric approach to study the interaction of amyloid β peptides with human α-2-macroglobulin.
Biochimie
December 2021
Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden. Electronic address:
We used MALDI-MS to study the interaction of amyloid β (Aβ) peptides with alpha-2-macroglobulin (α2M). The binding of amyloid beta (Aβ) peptides to alpha-2-macroglobulin (α2M) was found to inhibit the ability of trypsin to cleave out the peptide α2M 705-715 (Pep-α2M) from α2M. This was observed with both purified α2M and α2M in human serum.
View Article and Find Full Text PDFMet35 Oxidation Hinders Aβ25-35 Peptide Aggregation within the Dimyristoylphosphatidylcholine Bilayer.
ACS Chem Neurosci
September 2021
School of Systems Biology, George Mason University, Manassas, Virginia 20110, United States.
Using all-atom explicit solvent replica exchange molecular dynamics simulations, we studied the aggregation of oxidized (ox) Aβ25-35 peptides into dimers mediated by the zwitterionic dimyristoylphosphatidylcholine (DMPC) lipid bilayer. By comparing oxAβ25-35 aggregation with that observed for reduced and phosphorylated Aβ25-35 peptides, we elucidated plausible impact of post-translational modifications on cytotoxicity of Aβ peptides involved in Alzheimer's disease. We found that Met35 oxidation reduces helical propensity in oxAβ25-35 peptides bound to the lipid bilayer and enhances backbone fluctuations.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!