Copper levels are increased in the cerebral cortex and liver of APP and APLP2 knockout mice

被引:237
作者
White, AR
Reyes, R
Mercer, JFB
Camakaris, J
Zheng, H
Bush, AI
Multhaup, G
Beyreuther, K
Masters, CL
Cappai, R [1 ]
机构
[1] Univ Melbourne, Dept Pathol, Parkville, Vic 3052, Australia
[2] Mental Hlth Res Inst, Parkville, Vic 3052, Australia
[3] Royal Childrens Hosp, Murdoch Inst, Scobie & Claire Mackinnon Trace Elements Lab, Parkville, Vic 3052, Australia
[4] Deakin Univ, Sch Biol & Chem Sci, Ctr Cellular & Mol Biol, Burwood, Vic 3125, Australia
[5] Univ Melbourne, Dept Genet, Parkville, Vic 3052, Australia
[6] Merck & Co Inc, Merck Sharp & Dohme Res Labs, Dept Genet & Mol Biol, Rahway, NJ 07065 USA
[7] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA 02129 USA
[8] Univ Heidelberg, Ctr Mol Biol, D-69120 Heidelberg, Germany
[9] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Genet & Aging Unit, Charlestown, MA 02129 USA
基金
英国医学研究理事会;
关键词
metals; amyloid precursor protein; copper; oxidative stress; knockout;
D O I
10.1016/S0006-8993(99)01861-2
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
The pathological process in Alzheimer's disease (AD) involves amyloid beta (A beta) deposition and neuronal cell degeneration. The neurotoxic AP peptide is derived from the amyloid precursor protein (APP), a member of a larger gene family including the amyloid precursor-like proteins, APLP1 and APLP2. The APP and APLP2 molecules contain metal binding sites for copper and zinc. The zinc binding domain (ZnBD) is believed to have a structural rather than a catalytic role. The activity of the copper binding domain (CuBD) is unknown, however, APP reduces copper (IT) to copper (I) and this activity could promote copper-mediated neurotoxicity. The expression of APP and APLP2 in the brain suggests they could have an important direct or indirect role in neuronal metal homeostasis. To examine this, we measured copper, zinc and iron levels in the cerebral cortex, cerebellum and selected non-neuronal tissues from APP (APP(-/-)) and APLP2 (APLP2(-/-)) knockout mice using atomic absorption spectrophotometry. Compared with matched wild-type (WT) mice, copper levels were significantly elevated in both APP(-/-) and APLP2(-/-) cerebral cortex (40% and 16%, respectively) and liver (80% and 36%, respectively). Copper levels were not significantly different between knockout and WT cerebellum, spleen or serum samples. There were no significant differences observed between APP(-/-), APLP2(-/-) and WT mice zinc or iron levels in any tissue examined. These findings indicate APP and APLP2 expression specifically modulates copper homeostasis in the liver and cerebral cortex, the latter being a region of the brain particularly involved in AD. Perturbations to APP metabolism and in particular, its secretion or release from neurons may alter copper homeostasis resulting in increased A beta accumulation and free radical generation. These data support a novel mechanism in the APP/A beta pathway which leads to AD. (C) 1999 Elsevier Science B.V. All rights reserved.
引用
收藏
页码:439 / 444
页数:6
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