Different mechanisms of oxidative stress and neurotoxicity for Alzheimer's A beta(1--42) and A beta(25--35)
| Autor: | Christopher M. Lauderback, David Allan Butterfield, Jaroslaw Kanski, Marina V. Aksenova, Sridhar Varadarajan |
|---|---|
| Rok vydání: | 2001 |
| Předmět: |
Amyloid
Molecular Sequence Data Cell Culture Techniques Peptide Pharmacology medicine.disease_cause Biochemistry Catalysis Rats Sprague-Dawley chemistry.chemical_compound Colloid and Surface Chemistry Methionine Alzheimer Disease medicine Animals Humans Amino Acid Sequence Peptide sequence chemistry.chemical_classification Neurons Amyloid beta-Peptides Cell Death Chemistry Neurodegeneration Neurotoxicity Electron Spin Resonance Spectroscopy Proteins General Chemistry medicine.disease Peptide Fragments Amino acid Rats Microscopy Electron Oxidative Stress Nerve Degeneration Oxidation-Reduction Oxidative stress |
| Zdroj: | Journal of the American Chemical Society. 123(24) |
| ISSN: | 0002-7863 |
| Popis: | Oxidative stress induced by amyloid beta-peptide (A beta) has been implicated in the neurodegeneration observed in Alzheimer's disease (AD) brain. However, the mechanism by which the predominant form of A beta found in AD brains, A beta(1--42), causes oxidative stress and neurotoxicity remains unknown. Numerous laboratories have used the smaller 11-amino acid fragment of the full-length peptide, A beta(25--35), as a convenient alternative in AD investigations since the smaller peptide mimics several of the toxicological and oxidative stress properties of the native full-length peptide. Our observation that the truncated peptide is more rapidly toxic and causes more oxidative damage than the parent A beta(1--42) led us to investigate the cause for this enhanced toxicity of A beta(25--35) in order to gain insight into the mechanism of action of these peptides. These studies reveal that two different mechanisms may be operative in the two peptides; however, the single methionine residue in the peptides appears to play a crucial role in both mechanisms. That methionine is C-terminal in A beta(25--35) seems to be the cause for its exaggerated effects. When the next amino acid in the sequence of A beta(1--42) (valine) is appended to A beta(25--35), the resultant peptide, A beta(25--36), in which methionine is no longer C-terminal, is neither toxic to cultured neurons nor does it cause oxidative damage. Additionally, oxidizing the sulfur of methionine to a sulfoxide abrogates the damaging effects of both A beta(25--35) and A beta(1--42). The putative mechanistic role of methionine in the observed properties of A beta peptides is discussed in the context of the obtained results as is the role of A beta(1--42)-induced oxidative stress in the neurodegeneration found in AD brain. |
| Databáze: | OpenAIRE |
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