Explore The Roles And Their Molecular Mechanisms Of Two Selenium-containing Compounds In Alzheimer’s Disease

Alzheimer’s disease(AD), a neurodegenerative disease with the main manifestation of intellectual deterioration, is the main reason leading to dementia. AD is characterized by two pathological protein deposits, the senile plaques composed mainly of amyloid-β(Aβ) peptide and the neurofibrillary tangles(NFT) which are bundles of paired helical filaments(PHF) of protein Tau. AD is highly related with oxidative stress, inflammation response and the dishomeostasis of metal ions. The detaled mechanisms of onset and development of AD is still unclear, and there is still no effective therapeutic drug for the treatment of AD. Previously, selenium and selenoproteins were found to be capable of regulating the redox balance and metal ions homeostasis, therefore they may have therapeutic potential for AD. In this thesis, we investigated the inhibitory act of selenoprotein P(Sel P) on the neurotoxicity triggered by metal-induced Tau aggregates. Furthermore, we studied the roles and their underlied molecular mechanisms of two organic selenium-containing compounds on AD.Selenoproteins are a group of special proteins that contain the 21 st amino acid Sec in their sequence. Sel P is expressed with high level in the brain, and reported to be associated with the onset and progression of AD; however the underlying detailed molecular mechanisms are still unclear. Besides Sec, Sel P has two His-rich motifs, which make it capable of inhibiting metal-indcued aggregation and toxicity of both Aβ and Tau. Here, we further studied the protective effect of Sel P on primarily cultured neurons against metal-Tau aggregates. We showed that copper associated Tau-R2 aggregates, decreased protein levels of Microtubule associated protein 2(MAP-2) and synaptophysin in the primarily cultured cortical neurons, reduced mitochondrial density and mobility in the axon, and as a consequence, impaired the growth probably also the function of neurons. We demonstrated that Sel P-H significantly attenuated Cu2+/Cu+-Tau-R2-induced impairments of synapse and mitochondrial movement in neurons and protected neurons.L-Se-methylselenocysteine(SMC), as a natural organic selenium containing compound,is found in many kinds of food. Ebselen, also known as PZ51, is a kind of organic selenium hetercyclic compound and has high glutathione peroxidase(GPX) activity. Organic selenium compounds have much lower toxicity than inorganic selenium compounds, and they possessed considerable antioxidation and antitumours activities. However, little is known on the effects of SMC and ebselen in neurodegenerative diseases including AD.Upon SMC treatment, the intracellular ROS levels of N2A-SW were reduced dramatically, with the increase of cell viability. SMC decreased protein levels of APP, Bace-1, Tau-pt231 and Tau-ps404, but enhanced the expression of synaptophysin and PSD 95 in N2A-SW cells. In the primary neurons from 3×Tg AD mice, levels of APP, Aβ, Tau-pt231 and Tau-ps404 were reduced upon SMC treatments. SMC promoted the distribution of synaptophysin and PSD 95 in neurons, especially in their neurites. Furhtermore, SMC significantly improved the cognitive ability of the 3×Tg AD mice; inhibited the hyperphosphorylation of Tau protein by decreasing GSK3β activity and increasing PP2 A activity; surpressed the oxidative stress and inflammatory response in the brain; relieved the synaptic damages of neurons; and inhibited metal deposition in the brain. Our work demonstrated that SMC has great potential in the therapy of AD.Ebselen showed similar effects as SMC. It promoted viability and dcreased the intracellular ROS concentration of N2A-SW. By reducing the activity of GSK3β and increaseing the activity of PP2 A, Ebselen decreased the phosphorylation level of Tau at Thr231. This drug also improved the protein levels of synaptophysin and PSD 95 in N2A-SW cells. In the primary neurons, the levels of both Aβ and Tau-ps396 were decreased upon the treatment of Ebselen, but it stimulated the expression of synaptophysin and PSD 95. Furhtermore, Ebselen inhibited the hyperphosphorylation of Tau protein, surpressed the oxidative stress in the brain and thus significantly improved the cognitive ability of the 3×Tg AD mice.Our work demonstrated that Sel P, SMC and Ebselen have great potentials in the therapy of AD.