Formation of hydrogen peroxide and hydroxyl radicals from Aβ and α-synuclein as a possible mechanism of cell death in Alzheimer's disease and Parkinson's disease

Brian J. Tabner, Stuart Turnbull, Omar Ali El-Agnaf, David Allsop

Research output: Contribution to journalReview article

206 Citations (Scopus)

Abstract

The formation of extracellular or intracellular deposits of amyloid-like protein fibrils is a prominent pathological feature of many different neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). In AD, the β-amyloid peptide (Aβ) accumulates mainly extracellularly at the center of senile plaques, whereas, in PD, the α-synuclein protein accumulates within neurons inside the Lewy bodies and Lewy neurites. We have shown recently that solutions of Aβ 1-40, Aβ 1-42, Aβ 25-35, α-synuclein and non-Aβ component (NAC; residues 61-95 of α-synuclein) all liberate hydroxyl radicals upon incubation in vitro followed by the addition of small amounts of Fe(II). These hydroxyl radicals were readily detected by means of electron spin resonance spectroscopy, employing 5,5-dimethyl-1-pyrroline N-oxide (DMPO) as a spin trapping agent. Hydroxyl radical formation was inhibited by the inclusion of catalase or metal-chelators during Aβ or α-synuclein incubation. Our results suggest that hydrogen peroxide accumulates during the incubation of Aβ or α-synuclein, by a metal-dependent mechanism, and that this is subsequently converted to hydroxyl radicals, on addition of Fe (II), by Fenton's reaction. Consequently, one of the fundamental molecular mechanisms underlying the pathogenesis of cell death in AD and PD, and possibly other neurodegenerative or amyloid diseases, could be the direct production of hydrogen peroxide during formation of the abnormal protein aggregates.

Original languageEnglish
Pages (from-to)1076-1083
Number of pages8
JournalFree Radical Biology and Medicine
Volume32
Issue number11
DOIs
Publication statusPublished - 1 Jun 2002
Externally publishedYes

Fingerprint

Synucleins
Cell death
Hydroxyl Radical
Hydrogen Peroxide
Parkinson Disease
Alzheimer Disease
Cell Death
Amyloid
Metals
Spin Trapping
Amyloidogenic Proteins
Lewy Bodies
Amyloid Plaques
Electron Spin Resonance Spectroscopy
Neurites
Chelating Agents
Neurodegenerative diseases
Electron spin resonance spectroscopy
Neurodegenerative Diseases
Catalase

Keywords

  • Alzheimer's disease
  • Amyloid
  • Free radicals
  • Hydrogen peroxide
  • Neurodegeneration
  • Oxidative stress
  • Parkinson's disease

ASJC Scopus subject areas

  • Medicine(all)
  • Toxicology
  • Clinical Biochemistry

Cite this

Formation of hydrogen peroxide and hydroxyl radicals from Aβ and α-synuclein as a possible mechanism of cell death in Alzheimer's disease and Parkinson's disease. / Tabner, Brian J.; Turnbull, Stuart; Ali El-Agnaf, Omar; Allsop, David.

In: Free Radical Biology and Medicine, Vol. 32, No. 11, 01.06.2002, p. 1076-1083.

Research output: Contribution to journalReview article

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AB - The formation of extracellular or intracellular deposits of amyloid-like protein fibrils is a prominent pathological feature of many different neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). In AD, the β-amyloid peptide (Aβ) accumulates mainly extracellularly at the center of senile plaques, whereas, in PD, the α-synuclein protein accumulates within neurons inside the Lewy bodies and Lewy neurites. We have shown recently that solutions of Aβ 1-40, Aβ 1-42, Aβ 25-35, α-synuclein and non-Aβ component (NAC; residues 61-95 of α-synuclein) all liberate hydroxyl radicals upon incubation in vitro followed by the addition of small amounts of Fe(II). These hydroxyl radicals were readily detected by means of electron spin resonance spectroscopy, employing 5,5-dimethyl-1-pyrroline N-oxide (DMPO) as a spin trapping agent. Hydroxyl radical formation was inhibited by the inclusion of catalase or metal-chelators during Aβ or α-synuclein incubation. Our results suggest that hydrogen peroxide accumulates during the incubation of Aβ or α-synuclein, by a metal-dependent mechanism, and that this is subsequently converted to hydroxyl radicals, on addition of Fe (II), by Fenton's reaction. Consequently, one of the fundamental molecular mechanisms underlying the pathogenesis of cell death in AD and PD, and possibly other neurodegenerative or amyloid diseases, could be the direct production of hydrogen peroxide during formation of the abnormal protein aggregates.

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