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Copper induces the accumulation of amyloid-beta in the brain

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Abstract

Accumulation of amyloid beta protein (Aβ) plays a major role in the etiology of Alzheimer’s disease (AD). Aβ is generated from the cleavage of amyloid precursor protein (APP) by beta-site APP-cleaving enzyme 1 (BACE1). There are two factors that reduce of Aβ accumulation in the brain; degradation by peptidases such as neprilysin (NEP) and clearance via two transporters. The low-density lipoprotein receptor related protein 1 (LRP1) is the major transporter that clears Aβ from brain to blood and the receptor for advanced glycation end products (RAGE) is a receptor that transports Aβ from blood to brain. Copper (Cu) has been postulated to play a role in the pathogenesis of AD, especially involved in Aβ aggregation and toxicity. According to a recent study, Cu(II) could reduce Aβ clearance from the brain in cholesterol-fed rabbits. However, the critical mechanism is unclear. This study was purposed to demonstrate whether Cu (II) would alter accumulation of Aβ in brain. We treated 25 and 50 μM CuSO4 for 48-hour in the well-defined neurodevelopmental cell line (PC12), rat choroidal epithelial cell line (Z310), and rat brain endothelial cell line (RBE4) to estimate the effects on Cu(II) exposure in the brain.

Cu(II) increased the levels of Aβ(40) and Aβ(42) in the PC12 cell medium in a dose-dependent manner compared with control. The mRNA and protein expression levels of APP and BACE1, which play an important role in Aβ generation, were increased in the PC12 cells exposed to Cu(II). NEP expression levels in mRNA and protein were decreased in a dose-dependent manner in PC12 cells treated with Cu(II). In the RBE4 cells, Cu(II) decreased LRP1 levels and increased RAGE levels in mRNA and protein compared with control. Moreover, Cu(II) decreased the clearance of Aβ using the blood-brain barrier (BBB) transport study. However, in the Z310 cells, Cu(II) didn’t change the levels of LRP1 and RAGE in mRNA and protein. These results implied that Cu(II) increased Aβ accumulation in the brain by increasing Aβ production but decreasing Aβ degradation in the brain parenchyma and interfering with clearance of Aβ via the BBB.

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Authors and Affiliations

  1. Department of Preventive Medicine, College of Medicine, Chung-Ang University, Seoul, Korea

    Dong-Kyeong Kim, Ji-Won Song, Jung-Duck Park & Byung-Sun Choi

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Correspondence to Byung-Sun Choi.

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Kim, DK., Song, JW., Park, JD. et al. Copper induces the accumulation of amyloid-beta in the brain. Mol. Cell. Toxicol. 9, 57–66 (2013). https://doi.org/10.1007/s13273-013-0009-0

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