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Mechanochemical mechanism for peptidyl free radical generation by amyloid fibrils
1Department of Biochemistry and Molecular Biology, University of South Florida College of Medicine, Tampa 33612, USA. ckay@com 1.med.usf.edu
Abstract:
beta-Amyloid peptides (A beta) form the core of Alzheimer's disease (AD) senile plaques, and are implicated in AD neurotoxicity. A beta and some derivatives generate free radicals upon fibrilogenesis. A mechanism for free radical generation is proposed, based upon fibril cross beta-sheet structure: (1) During fibrilogenesis there is a small probability of mispacking of A beta monomers, resulting in abnormal fibril packing. (2) Continued fibrilogenesis traps a packing defect within the beta-sheet. Surrounding beta-sheet resists distortion, and the abnormally packed polypeptide(s) is strained. (3) Thermal processes cause homolytic bond scission and radical production from strained polypeptide through mechanically activated thermal decomposition. (4) Reaction with oxygen produces peroxy radicals, prevents unproductive radical recombination, and promotes observed cross-linking, production of reactive oxygen species and peptide fragmentation. Adiabatic mapping suggested significant strain would be generated by beta-sheet misalignment. The mechanism relates the common structure of fibrils to radical production, and may be relevant to cytotoxicity in prion and other amyloidoses.
Insights
Alzheimer's disease (AD) senile plaques contain beta-amyloid peptides (A beta) that generate free radicals. A proposed mechanism links abnormal fibril packing during A beta fibrilogenesis to radical production and neurotoxicity.
Area of Science:
- Biochemistry
- Neuroscience
- Molecular Biology
Background:
- Beta-amyloid peptides (A beta) aggregate into senile plaques, a hallmark of Alzheimer's disease (AD).
- A beta aggregation and its derivatives are implicated in AD-associated neurotoxicity.
- Free radical generation during A beta fibrilogenesis is a key factor in AD pathogenesis.
Purpose of the Study:
- To elucidate the mechanism of free radical generation during beta-amyloid peptide fibrilogenesis.
- To correlate the cross beta-sheet structure of A beta fibrils with radical production.
- To investigate the relevance of this mechanism to cytotoxicity in AD and other amyloidoses.
Main Methods:
- Analysis of beta-sheet structure in A beta fibrils.
- Adiabatic mapping to assess strain in mispacked beta-sheets.
- Mechanistic modeling of radical generation pathways.
Main Results:
- A mechanism for free radical generation linked to abnormal packing of A beta monomers within beta-sheet structures is proposed.
- Misfolding and packing defects during fibrilogenesis create strained polypeptide segments.
- Thermal decomposition of strained segments, followed by reaction with oxygen, leads to peroxy radical formation, cross-linking, reactive oxygen species production, and peptide fragmentation.
Conclusions:
- The study proposes a novel mechanism for free radical generation directly related to the common cross beta-sheet structure of amyloid fibrils.
- This mechanism explains the link between A beta fibril structure, radical production, and neurotoxicity in Alzheimer's disease.
- The findings may also be relevant to understanding cytotoxicity in other amyloid-related diseases, such as prion diseases.