title: Nucleic acid oxidative damage in Alzheimer's disease-explained by the hepcidin-ferroportin neuronal iron overload hypothesis?
abstract: There is strong literature support for brain metal dysregulation, oxidative stress and oxidative damage to neurons in Alzheimer's disease (AD); these processes begin early and continue throughout the disease. Here, we review current knowledge on metal dysregulation and nucleic acid oxidative damage in AD (we also include new data demonstrating increased RNA and DNA oxidative damage in hippocampus from individuals having suffered from degenerative (e.g. AD) and psychological diseases: 8-oxo-7,8-dihydroguanine (8-oxoGua) levels as determined by HPLC-EC-UV were particularly elevated in RNA and heterogeneously distributed among adjacent regions versus the control). Whereas neuronal iron accumulation occurs in aging, neuronal iron levels further increase in AD accompanied by oxidative damage, decreased copper levels, amyloid plaque formation and brain inflammation. The 'hepcidin-ferroportin iron overload' AD hypothesis links these processes together and is discussed here. Moreover, we find that most existing transgenic animal AD models only partly involve these processes, rather they are often limited to expression of mutated amyloid beta protein precursor (AbetaPP), presenilin, tau or apolipoprotein E proteins although a few models appear more relevant than others. Relevant models are likely to be crucial for refining and testing this hypothesis as well as developing new drugs.
authors.affiliation: Department of Toxicology and Risk Assessment, Infection Control and Environmental Health, The Norwegian Institute of Public Health, Oslo, Norway. Electronic address: tim.hofer@fhi.no.
authors.forename: Tim
authors.initials: T
authors.lastname: Hofer
authors.affiliation: UTSA Neurosciences Institute and Department of Biology, College of Sciences, University of Texas at San Antonio, San Antonio, TX, United States.
authors.forename: George
authors.initials: G
authors.lastname: Perry
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D027682:Cation Transport Proteins / Q000378:metabolism*; D064451:Hepcidins / Q000378:metabolism*; D006801:Humans; D019190:Iron Overload / Q000378:metabolism* / Q000473:pathology; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009696:Nucleic Acids / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D000098742:Ferroportin
chemical_list: D027682:Cation Transport Proteins; D064451:Hepcidins; D009696:Nucleic Acids; D000098742:Ferroportin
keywords: Anoxic encephalopathy; Copper; IL-6; Multi-infarct dementia; Parkinson’s disease; Schizophrenia