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

The pathological process in Alzheimer's disease (AD) involves amyloid beta (A beta) deposition and neuronal cell degeneration. The neurotoxic AP pepti de is derived from the amyloid precursor protein (APP), a member of a large r gene family including the amyloid precursor-like proteins, APLP1 and APLP 2. The APP and APLP2 molecules contain metal binding sites for copper and z inc. 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 APLP 2 in the brain suggests they could have an important direct or indirect rol e in neuronal metal homeostasis. To examine this, we measured copper, zinc and iron levels in the cerebral cortex, cerebellum and selected non-neurona l tissues from APP (APP(-/-)) and APLP2 (APLP2(-/-)) knockout mice using at omic absorption spectrophotometry. Compared with matched wild-type (WT) mic e, copper levels were significantly elevated in both APP(-/-) and APLP2(-/- ) cerebral cortex (40% and 16%, respectively) and liver (80% and 36%, respe ctively). Copper levels were not significantly different between knockout a nd WT cerebellum, spleen or serum samples. There were no significant differ ences observed between APP(-/-), APLP2(-/-) and WT mice zinc or iron levels in any tissue examined. These findings indicate APP and APLP2 expression s pecifically modulates copper homeostasis in the liver and cerebral cortex, the latter being a region of the brain particularly involved in AD. Perturb ations to APP metabolism and in particular, its secretion or release from n eurons may alter copper homeostasis resulting in increased A beta accumulat ion and free radical generation. These data support a novel mechanism in th e APP/A beta pathway which leads to AD. (C) 1999 Elsevier Science B.V. All rights reserved.