Evaluation of Time-Dependent Effects of Aluminum Exposure on Synaptic Impairment

Abstract

Aluminum (Al) is a ubiquitous metal and a well-known neurotoxicant, that not only causes multiple brain pathologies but also serves as a risk factor for many neurodegenerative disorders and Alzheimer’s disease-like symptoms. Al exposure through drinking water is responsible for hampering cognitive processes such as learning and memory. The neurotoxic effects of Al have been well documented on the brain, however, Al exposure in a time-dependent manner and post-exposure self recovery still needs to be elaborated. The current study aims to compare 1) the time dependent effects of Al exposure (keeping total exposure of 5850 mg/kg) in two durations, 30 and 45 days, and 2) to compare the post-exposure self-recovery effects after 20 days in both groups (30 and 45 days exposure). Rats were given 130 and 195 mg/kg of AlCl3.6H2O for 45 and 30 days respectively, to see the time-dependent exposure effect. At the end of exposure, rats were given distilled water and allowed to self-recover for 20 days to study the recovery in these groups. Oxidative stress markers and neurotransmitter levels (noradrenaline, dopamine, serotonin, and acetylcholine) were measured for exposure and recovery groups. Expression of different synaptic genes (Synaptophysin, SNAP25, Neurexin 1/2, PSD95, Shank1/2, Homer1, CamkIV, Neuregulin 1/2, and Kalirin) were measured using qPCR and compared in the Al exposure and post-exposure recovery groups. To understand the mechanism of Al exposure and recovery, cellular morphology, immunohistochemical analysis of synaptophysin (Syp), glial fibrillary acidic protein (GFAP), cell proliferation (Ki67), and estrogen receptor alpha (ERα) of the rat brain cortex and hippocampus were performed. Damage in lipid and protein functional Abstract xix groups was measured through FTIR. Moreover, fluorescence analysis of NADH and FAD of the rat brain cortex and the hippocampus were also investigated in all studied groups. Results showed that oxidative stress-induced damage reduced neurotransmitter levels and their respective metabolites in Al exposure groups. Data showed downregulation of synaptic gene mRNA expression, decreased Syp, Ki67, ERα immunoreactivity, increased GFAP immunostaining with plaque deposition, and impaired cellular morphology. Al exposure groups also showed disorganization in protein and lipid functional groups by increasing membrane fluidity, which causes disorientation in the secondary structure of protein after both exposure periods. However, better improvement/recovery in these parameters was observed in the recovery group of 30 days Al exposure compared to the 45 days Al exposure group. Study results suggested that short-term exposure resulted in a better restoration of studied parameters after time-dependent Al exposure than prolonged exposure. Current study findings provide insight into the harmful effects of Al exposure. This can be employed for future preventive and therapeutic strategies against Al neurotoxicity, either through endogenous preventive mechanisms or through antioxidative strategies.