Mercury-induced amyloid-beta (Aβ) accumulation in the brain is mediated by disruption of Aβ transport

According to a recent study, mercury (Hg) exposure contributes to Alzheimer's disease (AD). However, the underlying mechanisms are not understood. This study investigated the effect of methylmercury (MeHg) treatment on the generation, degradation, and transport of amyloid beta-protein (A beta) in the brain. Wistar rats were administered MeHg by gavage (0, 20, 200, and 2,000 mu g Hg/kg/day) for 4 weeks. The total Hg in the blood and brain regions was measured, and the levels of A beta(42) in plasma, cerebrospinal fluid (CSF), and brain regions were estimated. The expression of amyloid precursor protein (APP), beta-site APP-cleaving enzyme 1 (BACE1), and neprilysin (NEP) in the brain regions was determined, in addition to the expression of low-density lipoprotein receptor-related protein 1 (LRP1) and the receptor for advanced glycation end products (RAGE) in the brain capillary endothelium (BCE). Finally, the amount of soluble low-density lipoprotein receptor-related protein (sLRP) in the plasma was determined. A beta(42) levels were decreased in the CSF of the 2,000 mu g Hg/kg/day group compared with controls, and A beta(42) levels increased in the hippocampus (HC) in a dose-dependent manner. MeHg decreased LRP1 expression but increased RAGE levels in BCE. sLRP levels were decreased in the plasma of the MeHg-treated rats. They were positively correlated with CSF A beta(42) and negatively correlated with A beta(42) and Hg levels in HC. These results imply that MeHg reduces the transportation of A beta, thereby resulting in the accumulation of the protein in the HC. Plasma sLRP levels may be an early biomarker of Hg-induced A beta accumulation in the brain.