Cognitive Protective Effect Of N-Stearoyl-L-Tyrosine On Tau Transgenic Mice And Its Mechanism Of Anti-cell Aging And Apoptosis

Although it has spent a lot of energy and money on investing the development of Alzheimer’s disease for Aβprotein,but still no drug treatment can cure or even delay the onset of Alzheimer’s disease.The neurofibrillary tangles formed by the abnormal modification of the microtubule-associated protein tau are a significant pathological marker in the pathogenesis of AD.Thus,Tau plays an important role in tissue damage in neural refinement.Therefore,the intervention for tau protein abnormal modification can effectively improve the efficacy of AD treatment.At the same time,there is growing evidence showed that oxidative stress and free radical damage are closely associated with Alzheimer’s disease（AD）.N-stearoyl-L-tyrosine（Ns Tyr）,a synthetic new endogenous cannabinoid analogue,is not only similar to cannabinoids（AEA）in structure and even function,has a good neuroprotective effect.Based on the molecular level,human embryonic kidney 293 cells（HEK 293）were transfected with the Tau 411 plasmid to evaluate the effect of tau protein on cell viability.Added 50μM H₂O₂ to simulate oxidative stress（OS）microenvironment.The apparent senescence and apoptosis were observed in HEK293/tau cells incubated with 50μM H₂O₂ byβ-galactosidase aging staining and flow cytometry.The expression of PRb-P16 and P53were also up-regulated after incubation with 50μM H₂O₂,and the expression of anti-apoptotic protein Bcl-2 was down-regulated.The expression of PRb-P16 and P53 was down-regulated and the expression of Bcl2 was up-regulated,and it was dose-dependent in the presence of Ns Tyr.After blockade of CB1 and CB2 receptors,CB2 receptor antagonist AM630 reverses Ns Tyr antagonizes oxidative stress-induced senescence and apoptosis,suggesting that Ns Tyr plays a role via CB2 receptors.Meanwhile,the results of transfection of si RNA_CB2 group also reversed Ns Tyr antagonized oxidative stress-induced senescence and apoptosis,and confirmed that CB2 receptor plays an important role in Ns Tyr resistance to oxidative stress-induced cell senescence and apoptosis.Based on the animal level,the protective effect of Ns Tyr was investigated on the tau transgenic mouse model and the mechanism was studied.11-month-old Tau transgenic mice were randomized to receive different doses of Nstyr（15-45 mg/kg）.one month later,from the opening experiment,the elevated cross maze test and the water maze test results,it showed Ns Tyr significant improve the cognitive level of Tau transgenic mice.The expression of PRb-P16 and P53 in Ns Tyr group was significantly down-regulated.Suggesting that Ns Tyr can delay senescence.To sum up,at the molecular level,Ns Tyr can be resistant to oxidative stress hardening of senescence and apoptosis via CB2 receptor.At the animal level,Ns Tyr can delay senescence and improve the cognitive level of Tau transgenic mice.