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

Abstract

-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 β-protein (Aβ) in the brain. Wistar rats were administered MeHg by gavage (0, 20, 200, and 2,000 μg Hg/kg/day) for 4 weeks. The total Hg in the blood and brain regions was measured, and the levels of Aβ 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. Aβ 42 levels were decreased in the CSF of the 2,000 μg Hg/kg/day group compared with controls, and Aβ 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 MeHgtreated rats. They were positively correlated with CSF Aβ 42 and negatively correlated with Aβ 42 and Hg levels in HC. These results imply that MeHg reduces the transportation of Aβ, thereby resulting in the accumulation of the protein in the HC. Plasma sLRP levels may be an early biomarker of Hg-induced Aβ accumulation in the brain.

Mercury and Alzheimer’s Disease: Hg(II) Ions Display Specific Binding to the Amyloid-β Peptide and Hinder Its Fibrillization

“…Hg exposure furthermore increased the release of Aβ in SHSY5Y neuroblastoma cells [87], which may promote Aβ aggregation. In Wistar rats exposed to MeHg, the Aβ levels increased in the hippocampus but decreased in the CSF, likely due to impaired Aβ transport [159]. Increased production of AβPP and decreased production of the Aβ-clearing enzyme neprilysin was observed in PC12 cells exposed to Hg(II) and MeHg [89].…”

Fungicide Residues Exposure and β-amyloid Aggregation in a Mouse Model of Alzheimer’s Disease

“…Furthermore, an acute injection of lead [27 mg=kg via the intraperitoneal (ip) route] in a mouse model of Alzheimer's disease (APP V717F) has resulted in a lower expression of LRP1 in the choroid plexus than injection of vehicle (Gu et al 2011). Mercury was shown to be involved in the disruption of Ab peptide clearance pathways both in vivo [in rats: 2 mg=kg per day for 4 weeks by gavage (Kim et al 2014)] and in vitro [in SH-SY5Y cells: 10 and 20 lM (Chin-Chan et al 2015)]. Moreover, rats orally treated with aluminum (20 g=d, twice a week) through diet, from 6 months of age until the end of their life and who developed cognitive deficits, presented an epidemiological standpoint, it is difficult to assess the impact of a long-term exposure to pesticide residues on neurodegenerative diseases such as Alzheimer's disease.…”

Toxicology of organic-inorganic hybrid molecules: bio-organometallics and its toxicology

“…and metalloids. Such studies published these past three years in the Journal of Toxicological Sciences investigated the toxicity of many types of metals, including cadmium (Ohtani et al, 2013;Miura et al, 2013;Baba et al, 2014;Du et al, 2014;Park et al, 2015;Lukkhananan et al, 2015), mercury (Yoshida et al, 2013;Kim et al, 2014), methylmercury (Hwang et al, 2013a(Hwang et al, , 2013bIwai-Shimada et al, 2013;Chang et al, 2013;Hirooka et al, 2013;Kim et al, 2013;Watanabe et al, 2013;Shao et al, 2015;Toyama et al, 2015), aluminum (Zhang et al, 2013;Jinzhu et al, 2015), manganese (Fujishiro et al, 2013), uranium (Lestaevel et al, 2013), arsenic (Tokumoto et al, 2013;Wang et al, 2015), arsine (Kato et al, 2014), organic bismuth (Kohri et al, 2015), chromium (Kimura et al, 2015), and tributyltin (Oyanagi et al, 2015). Although methylmercury is one of the organic-inorganic hybrid molecules (the minimum unit!…”