Copper induces the accumulation of amyloid-beta in the brain

초록

Accumulation of amyloid beta protein (A beta) plays a major role in the etiology of Alzheimer's disease (AD). A beta 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 A beta 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 A beta from brain to blood and the receptor for advanced glycation end products (RAGE) is a receptor that transports A beta from blood to brain. Copper (Cu) has been postulated to play a role in the pathogenesis of AD, especially involved in A beta aggregation and toxicity. According to a recent study, Cu(II) could reduce A beta 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 A beta in brain. We treated 25 and 50 mu M 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 A beta(40) and A beta(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 A beta 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 A beta using the blood-brain bather (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 A beta accumulation in the brain by increasing A beta production but decreasing A beta degradation in the brain parenchyma and interfering with clearance of A beta via the BBB.

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