A Systemic Research Of Sodium Selenate Treats Alzheimer’s Disease

Alzheimer’s disease(AD) is one of the neurodegenerative disorders causing memory and cognitive dysfunction in the elderly. Amyloid-β deposition and hyperphosphorylation of tau protein are currently considered as two main pathological features of AD. Until now the detailed mechanism underling the pathogenesis of AD remains unknown. Current therapies and drugs used in the treatment of AD can only alleviate the symptoms of AD without healing it.Recently, increasing evidences have revealed that selenium plays a criticle role in AD prevention. Sodium selenate is much less toxic than other inorganic selenium compounds such as sodium selenite. Meanwhile, it has higher ability to activate protein phosphatase(PP2A). Thus, 3×Tg triple transgenic mice(Psen1, APPSwe, tau P301L) were used as an animal model of AD in this study. AD mice were treated with sodium selenate dissolved in the drinking water at a final concentration of 6μg / m L from the age of 8 weeks. The effect of sodium selenate on the pathogenesis of AD was investigated at different age, and the underlying mechanism was studied extensively.For the first time, PET was used to study the pharmacological mechanism of selenate in AD prevention. We observed a decreased uptake of 18 FDG in the brain of AD mice with senescence. Moreover, mice with long-term treatment of selenate showed a much lower absoprtion rate of 18 FDG than controls. We detected the spatial learning and memory ability of mice at different age by the method of Morris water maze and found that the escape latency was much shorter in the selenate-treated mice compared with the control mice with the same age. After stopping space navigation test, the selenate-treated group demonstrated a better result in long-term memory performance as compared to the control group. These data suggest that selenate can restore the long-term memory of AD mice.Subsequent histopathological study showed that the three transgenic AD mice had a decreased amount of Nissl body with the increase of age. Administration of selenate restored the amount of Nissl bodies in the hippocampus of mice compared with the control mice with the same age. We also found that treatment with selenate led to a significantly reduced expression of BACE1 in the hippocampus of mice at 6- and 12-month of age, with comparison to the control mice. By stainning the senile plaques with thioflavin T we found that selenate-treated mice had less senile plaques than the control mice at the same age. Subsequently, we quantified Aβ1-42 by ELISA and found that sodium selenate reduced this main cause of senile plaques significantly. We also proved that selenate not only had an effect on prevention of tau hyperphosphorylation, but also inhibed the activity of BACE1. The major proteins in the Akt / GSK3β pathway were also detected and quantified by Western blot analysis. Results showed that selenate regulate this pathway by the activition of PP2 A, which confirms the results published previously.Astrocytes are considered to be co-localized with senile plaques and may have the function of phagocytic of amyloid deposition. We detected the increased expression of GFAP in the selenate-treated mice compared with the control mice. Meanwhile, we also found that the NO level of selenate-treated mice was increased compared with the control group, which indicates that selenate can activate gliocytes and plays a benefit role in reduction of extracellular Aβ deposition.The transcriptomes of mice hippocampuses were sequenced in the control and selenate-treated groups with different ages using the PSTAR II plus sequencing platform. We found that selenate treatment made an intervention to AD pathology by targeting some important genes, such as the Gsx2 and Olfr families, Tsacc etc.SR-μXRF and ICP-MS were also used for imaging and quantifing the quantities of metal ions in mice brains. It was found that AD mice brain enriched the metal ions such as Fe, Cu, Zn ions with aging. Sodium selenate could prevent metal ions accumulation in mice brain, thus influenced the process of AD formation.