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Overexpression of Alzheimer's disease amyloid-beta opposes the age-dependent elevations of brain copper and iron.

Abstract

Increased brain metal levels have been associated with normal aging and a variety of diseases, including Alzheimer's disease (AD). Copper and iron levels both show marked increases with age and may adversely interact with the amyloid-beta (Abeta) peptide causing its aggregation and the production of neurotoxic hydrogen peroxide (H(2)O(2)), contributing to the pathogenesis of AD. Amyloid precursor protein (APP) possesses copper/zinc binding sites in its amino-terminal domain and in the Abeta domain. Here we demonstrate that overexpression of the carboxyl-terminal fragment of APP, containing Abeta, results in significantly reduced copper and iron levels in transgenic mouse brain, while overexpression of the APP in Tg2576 transgenic mice results in significantly reduced copper, but not iron, levels prior to the appearance of amyloid neuropathology and throughout the lifespan of the mouse. Concomitant increases in brain manganese levels were observed with both transgenic strains. These findings, complemented by our previous findings of elevated copper levels in APP knock-out mice, support roles for APP and Abeta in physiological metal regulation.

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  • Authors+Show Affiliations

    ,

    Department of Pathology, The University of Melbourne, Victoria 3010, Australia.

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    Source

    The Journal of biological chemistry 277:47 2002 Nov 22 pg 44670-6

    MeSH

    Aging
    Alzheimer Disease
    Amyloid beta-Peptides
    Amyloid beta-Protein Precursor
    Animals
    Brain
    Cobalt
    Copper
    Female
    Homeostasis
    Humans
    Iron
    Male
    Manganese
    Mice
    Mice, Inbred Strains
    Mice, Transgenic
    Zinc

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't
    Research Support, U.S. Gov't, P.H.S.

    Language

    eng

    PubMed ID

    12215434

    Citation

    Maynard, Christa J., et al. "Overexpression of Alzheimer's Disease Amyloid-beta Opposes the Age-dependent Elevations of Brain Copper and Iron." The Journal of Biological Chemistry, vol. 277, no. 47, 2002, pp. 44670-6.
    Maynard CJ, Cappai R, Volitakis I, et al. Overexpression of Alzheimer's disease amyloid-beta opposes the age-dependent elevations of brain copper and iron. J Biol Chem. 2002;277(47):44670-6.
    Maynard, C. J., Cappai, R., Volitakis, I., Cherny, R. A., White, A. R., Beyreuther, K., ... Li, Q. X. (2002). Overexpression of Alzheimer's disease amyloid-beta opposes the age-dependent elevations of brain copper and iron. The Journal of Biological Chemistry, 277(47), pp. 44670-6.
    Maynard CJ, et al. Overexpression of Alzheimer's Disease Amyloid-beta Opposes the Age-dependent Elevations of Brain Copper and Iron. J Biol Chem. 2002 Nov 22;277(47):44670-6. PubMed PMID: 12215434.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Overexpression of Alzheimer's disease amyloid-beta opposes the age-dependent elevations of brain copper and iron. AU - Maynard,Christa J, AU - Cappai,Roberto, AU - Volitakis,Irene, AU - Cherny,Robert A, AU - White,Anthony R, AU - Beyreuther,Konrad, AU - Masters,Colin L, AU - Bush,Ashley I, AU - Li,Qiao-Xin, Y1 - 2002/09/04/ PY - 2002/9/7/pubmed PY - 2003/1/8/medline PY - 2002/9/7/entrez SP - 44670 EP - 6 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 277 IS - 47 N2 - Increased brain metal levels have been associated with normal aging and a variety of diseases, including Alzheimer's disease (AD). Copper and iron levels both show marked increases with age and may adversely interact with the amyloid-beta (Abeta) peptide causing its aggregation and the production of neurotoxic hydrogen peroxide (H(2)O(2)), contributing to the pathogenesis of AD. Amyloid precursor protein (APP) possesses copper/zinc binding sites in its amino-terminal domain and in the Abeta domain. Here we demonstrate that overexpression of the carboxyl-terminal fragment of APP, containing Abeta, results in significantly reduced copper and iron levels in transgenic mouse brain, while overexpression of the APP in Tg2576 transgenic mice results in significantly reduced copper, but not iron, levels prior to the appearance of amyloid neuropathology and throughout the lifespan of the mouse. Concomitant increases in brain manganese levels were observed with both transgenic strains. These findings, complemented by our previous findings of elevated copper levels in APP knock-out mice, support roles for APP and Abeta in physiological metal regulation. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/12215434/Overexpression_of_Alzheimer's_disease_amyloid_beta_opposes_the_age_dependent_elevations_of_brain_copper_and_iron_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=12215434 DB - PRIME DP - Unbound Medicine ER -