Overexpression of Alzheimer's disease amyloid-beta opposes the age-dependent elevations of brain copper and iron.
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.
Maynard
Christa J
CJ
Department of Pathology, The University of Melbourne, Victoria 3010, Australia.
Cappai
Roberto
R
Volitakis
Irene
I
Cherny
Robert A
RA
White
Anthony R
AR
Beyreuther
Konrad
K
Masters
Colin L
CL
Bush
Ashley I
AI
Li
Qiao-Xin
QX
D000375:Aging / Q000502:physiology*; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000502:physiology*; D003035:Cobalt / Q000378:metabolism; D003300:Copper / Q000378:metabolism*; D005260:Female; D006706:Homeostasis; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008297:Male; D008345:Manganese / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D015032:Zinc / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D003035:Cobalt; D008345:Manganese; D003300:Copper; D007501:Iron; D015032:Zinc