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Metal dyshomeostasis and oxidative stress in Alzheimer's disease.

Abstract

Alzheimer's disease is the leading cause of dementia in the elderly and is defined by two pathological hallmarks; the accumulation of aggregated amyloid beta and excessively phosphorylated Tau proteins. The etiology of Alzheimer's disease progression is still debated, however, increased oxidative stress is an early and sustained event that underlies much of the neurotoxicity and consequent neuronal loss. Amyloid beta is a metal binding protein and copper, zinc and iron promote amyloid beta oligomer formation. Additionally, copper and iron are redox active and can generate reactive oxygen species via Fenton (and Fenton-like chemistry) and the Haber-Weiss reaction. Copper, zinc and iron are naturally abundant in the brain but Alzheimer's disease brain contains elevated concentrations of these metals in areas of amyloid plaque pathology. Amyloid beta can become pro-oxidant and when complexed to copper or iron it can generate hydrogen peroxide. Accumulating evidence suggests that copper, zinc, and iron homeostasis may become perturbed in Alzheimer's disease and could underlie an increased oxidative stress burden. In this review we discuss oxidative/nitrosative stress in Alzheimer's disease with a focus on the role that metals play in this process. Recent studies have started to elucidate molecular links with oxidative/nitrosative stress and Alzheimer's disease. Finally, we discuss metal binding compounds that are designed to cross the blood brain barrier and restore metal homeostasis as potential Alzheimer's disease therapeutics.

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  • Publisher Full Text
  • Authors+Show Affiliations

    ,

    The Mental Health Research Institute, The University of Melbourne, Victoria 3010, Australia.

    ,

    Source

    Neurochemistry international 62:5 2013 Apr pg 540-55

    MeSH

    Alzheimer Disease
    Homeostasis
    Humans
    Metals
    Nitric Oxide
    Oxidative Stress

    Pub Type(s)

    Journal Article
    Review

    Language

    eng

    PubMed ID

    22982299

    Citation

    Greenough, Mark A., et al. "Metal Dyshomeostasis and Oxidative Stress in Alzheimer's Disease." Neurochemistry International, vol. 62, no. 5, 2013, pp. 540-55.
    Greenough MA, Camakaris J, Bush AI. Metal dyshomeostasis and oxidative stress in Alzheimer's disease. Neurochem Int. 2013;62(5):540-55.
    Greenough, M. A., Camakaris, J., & Bush, A. I. (2013). Metal dyshomeostasis and oxidative stress in Alzheimer's disease. Neurochemistry International, 62(5), pp. 540-55. doi:10.1016/j.neuint.2012.08.014.
    Greenough MA, Camakaris J, Bush AI. Metal Dyshomeostasis and Oxidative Stress in Alzheimer's Disease. Neurochem Int. 2013;62(5):540-55. PubMed PMID: 22982299.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Metal dyshomeostasis and oxidative stress in Alzheimer's disease. AU - Greenough,Mark A, AU - Camakaris,James, AU - Bush,Ashley I, Y1 - 2012/09/08/ PY - 2012/06/01/received PY - 2012/08/13/revised PY - 2012/08/30/accepted PY - 2012/9/18/entrez PY - 2012/9/18/pubmed PY - 2013/10/18/medline SP - 540 EP - 55 JF - Neurochemistry international JO - Neurochem. Int. VL - 62 IS - 5 N2 - Alzheimer's disease is the leading cause of dementia in the elderly and is defined by two pathological hallmarks; the accumulation of aggregated amyloid beta and excessively phosphorylated Tau proteins. The etiology of Alzheimer's disease progression is still debated, however, increased oxidative stress is an early and sustained event that underlies much of the neurotoxicity and consequent neuronal loss. Amyloid beta is a metal binding protein and copper, zinc and iron promote amyloid beta oligomer formation. Additionally, copper and iron are redox active and can generate reactive oxygen species via Fenton (and Fenton-like chemistry) and the Haber-Weiss reaction. Copper, zinc and iron are naturally abundant in the brain but Alzheimer's disease brain contains elevated concentrations of these metals in areas of amyloid plaque pathology. Amyloid beta can become pro-oxidant and when complexed to copper or iron it can generate hydrogen peroxide. Accumulating evidence suggests that copper, zinc, and iron homeostasis may become perturbed in Alzheimer's disease and could underlie an increased oxidative stress burden. In this review we discuss oxidative/nitrosative stress in Alzheimer's disease with a focus on the role that metals play in this process. Recent studies have started to elucidate molecular links with oxidative/nitrosative stress and Alzheimer's disease. Finally, we discuss metal binding compounds that are designed to cross the blood brain barrier and restore metal homeostasis as potential Alzheimer's disease therapeutics. SN - 1872-9754 UR - https://www.unboundmedicine.com/medline/citation/22982299/Metal_dyshomeostasis_and_oxidative_stress_in_Alzheimer's_disease_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0197-0186(12)00281-1 DB - PRIME DP - Unbound Medicine ER -