title: The redox chemistry of the Alzheimer's disease amyloid beta peptide.
abstract: There is a growing body of evidence to support a role for oxidative stress in Alzheimer's disease (AD), with increased levels of lipid peroxidation, DNA and protein oxidation products (HNE, 8-HO-guanidine and protein carbonyls respectively) in AD brains. The brain is a highly oxidative organ consuming 20% of the body's oxygen despite accounting for only 2% of the total body weight. With normal ageing the brain accumulates metals ions such iron (Fe), zinc (Zn) and copper (Cu). Consequently the brain is abundant in antioxidants to control and prevent the detrimental formation of reactive oxygen species (ROS) generated via Fenton chemistry involving redox active metal ion reduction and activation of molecular oxygen. In AD there is an over accumulation of the Amyloid beta peptide (Abeta), this is the result of either an elevated generation from amyloid precursor protein (APP) or inefficient clearance of Abeta from the brain. Abeta can efficiently generate reactive oxygen species in the presence of the transition metals copper and iron in vitro. Under oxidative conditions Abeta will form stable dityrosine cross-linked dimers which are generated from free radical attack on the tyrosine residue at position 10. There are elevated levels of urea and SDS resistant stable linked Abeta oligomers as well as dityrosine cross-linked peptides and proteins in AD brain. Since soluble Abeta levels correlate best with the degree of degeneration [C.A. McLean, R.A. Cherny, F.W. Fraser, S.J. Fuller, M.J. Smith, K. Beyreuther, A.I. Bush, C.L. Masters, Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease, Ann. Neurol. 46 (1999) 860-866] we suggest that the toxic Abeta species corresponds to a soluble dityrosine cross-linked oligomer. Current therapeutic strategies using metal chelators such as clioquinol and desferrioxamine have had some success in altering the progression of AD symptoms. Similarly, natural antioxidants curcumin and ginkgo extract have modest but positive effects in slowing AD development. Therefore, drugs that target the oxidative pathways in AD could have genuine therapeutic efficacy.
authors: Department of Pathology, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors: Danielle G
authors: DG
authors: Smith
authors: Roberto
authors: R
authors: Cappai
authors: Kevin J
authors: KJ
authors: Barnham
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000627:therapeutic use; D002614:Chelating Agents / Q000627:therapeutic use; D003474:Curcumin / Q000627:therapeutic use; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D020441:Ginkgo biloba / Q000737:chemistry; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008670:Metals / Q000737:chemistry / Q000378:metabolism; D010084:Oxidation-Reduction; D010100:Oxygen / Q000737:chemistry / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D010936:Plant Extracts / Q000627:therapeutic use; D017382:Reactive Oxygen Species / Q000737:chemistry / Q000378:metabolism*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D002614:Chelating Agents; D004791:Enzyme Inhibitors; D008670:Metals; D010455:Peptides; D010936:Plant Extracts; D017382:Reactive Oxygen Species; D014443:Tyrosine; D004247:DNA; C007543:dityrosine; D003474:Curcumin; D010100:Oxygen