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Abstract:Concentrations of heavy metals, including mercury, have been shown to be altered in the brain and body fluids of Alzheimer's disease (AD) patients. To explore potential pathophysiological mechanisms we used an in vitro model system (SHSY5Y neuroblastoma cells) and investigated the effects of inorganic mercury (HgCl 2 ) on oxidative stress, cell cytotoxicity, ␤-amyloid production, and tau phosphorylation. We demonstrated that exposure of cells to 50 g/L (180 nM) HgCl 2 for 30 min induces a 30% reduction in cellular glutathione (GSH) levels (n ϭ 13, p Ͻ 0.001). Preincubation of cells for 30 min with 1 M melatonin or premixing melatonin and HgCl 2 appeared to protect cells from the mercury-induced GSH loss. Similarly, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MT T ) cytotoxicity assays revealed that 50 g/L HgCl 2 for 24 h produced a 50% inhibition of MT T reduction (n ϭ 9, p Ͻ 0.001). Again, melatonin preincubation protected cells from the deleterious effects of mercury, resulting in MT T reduction equaling control levels. The release of ␤-amyloid peptide (A␤) 1-40 and 1-42 into cell culture supernatants after exposure to HgCl 2 was shown to be different: A␤ 1-40 showed maximal (15.3 ng/ml) release after 4 h, whereas A␤ 1-42 showed maximal (9.3 ng/ml) release after 6 h of exposure to mercury compared with untreated controls (n ϭ 9, p Ͻ 0.001). Preincubation of cells with melatonin resulted in an attenuation of A␤ 1-40 and A␤ 1-42 release. Tau phosphorylation was significantly increased in the presence of mercury (n ϭ 9, p Ͻ 0.001), whereas melatonin preincubation reduced the phosphorylation to control values. These results indicate that mercury may play a role in pathophysiological mechanisms of AD. Key Words: Mercury-Oxidative stress-␤-Amyloid-TauMelatonin-SHSY5Y neuroblastoma cells.

The pineal secretory product melatonin has, in addition to regulating retinal, circadian and vascular functions, neuroprotective effects. Blood melatonin levels are often decreased in Alzheimer's disease (AD), a progressively disabling neurodegenerative disorder. In this study we provide the first immunohistochemical evidence for the localization of melatonin 1a-receptor (MT(1)) in aged human hippocampus and a comparison of AD cases. MT(1) was localized to pyramidal neurons in the hippocampal cornu ammonis (CA)1-4 subfields. There was a distinct increase in staining intensity in all AD cases indicating an up-regulation of the receptor, possibly as a compensatory response to impaired melatonin levels in order to augment melatonin's neuroprotective effects.

Background: β-Amyloid peptide (Aβ), a neutrotoxic substance, has been implicated to a great degree in cell death during the course of AD. Resveratrol, a natural polyphenol mainly found in red wine, has been shown to be cardioprotective and chemoprotective. Since a moderate wine intake correlates with a lower risk for Alzheimer disease (AD), an additional neuroprotective effect has been postulated for resveratrol. Objective: The present study aimed at elucidating the possible neuroprotective effects of resveratrol against Aβ-induced neurotoxicity. Methods: The neuroprotective capacity against Aβ-related oxidative stress was studied in a cell culture model suitable for studying such potentially neuroprotective substances. Results: Resveratrol maintains cell viability and exerts an anti-oxidative action by enhancing the intracellular free-radical scavenger glutathione. Conclusion: Our findings suggest that red wine may be neuroprotective through the actions of resveratrol.

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Melatonin is synthesized in the pineal gland and retina during the night. Retinal melatonin is believed to be involved in local cellular modulation and in regulation of light-induced entrainment of circadian rhythms. The present study provides the first immunohistochemical evidence for the localization of melatonin 1a-receptor (MT1) in human retina of aged subjects. Ganglion, amacrine, and photoreceptor cells expressed MT1. In addition, MT1 immunoreactivity was localized to cell processes in the inner plexiform layer and to central vessels of the retina, as well as to retinal vessels but not to ciliary or choroidal vessels. These results support a variety of cellular and vascular effects of melatonin in the human retina. Preliminary evidence from patients with Alzheimer's disease (AD) revealed increased MT1 immunoreactivity in ganglion and amacrine cells, as well as in vessels. In AD cases photoreceptor cells were degenerated and showed low MT1 expression.

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