?-lipoic Acid Inhibits Tau Hyperphosphorylation,Alleviates Cognitive Impairment And Its Mechanism In P301S Transgenic Mice

Tauopathies is a concept baced on the molecular level study of protein in recent years,and it refers to a series of neurodegenerative diseases characterized by the abnormal deposition of Tau protein,including Alzheimer's disease(AD),chronic traumatic encephalopathy,corticobasal degeneration and Pick's disease.AD is the most common tauopathies characterized by the neurofibrillary tangles(NFTs)which formed by hyperphosphorylation Tau.Reducing the overall levels of Tau or preventing its hyperphosphorylation and accumulation have been shown to have therapeutic benefits,although it remains unclear how Tau contributes to the dysfunction and degeneration involved in AD.Interestingly,in addition to Tau hyperphosphorylation,there is increasing evidence that oxidative stress is another pathological feature of tauopathies,while progressive iron accumulation in the normal aging brain and aberrant elevated iron in the AD brain has been identified as one of the causes of oxidative stress.Through Fenton's reaction,overloaded iron can generate excessive free radicals,which attack DNA,proteins,lipid membranes,damage cellular function and cause neuronal death.Particularly,iron can bind to Tau protein and trigger its hyperphosphorylation,eventually leading to the formation of NFTs.Thus,reducing the redox activity of the iron-Tau interaction may directly rescue the neurons,and this might be a potential therapy for treating tauopathy(including AD).?-Lipoic acid(LA)is a natural enzyme cofactor with antioxidant and iron chelator properties.Previous studies suggest that LA could stabilize the cognitive function of AD patients,and animal studies have confirmed its anti-amyloidogenic properties.However,the underlying mechanisms remain unclear,especially with respect to the ability of LA to control Tau pathology and neuronal damage.Here,we treated the P301S Tg mice with different concentrations of LA(3 mg/kg and 10 mg/kg)for 10 weeks by intraperitoneal injection,and the behavior test,morphology,molecular biology were employed to explore the efficacy and molecular mechanisms of LA on Tau pathology.The results were as followed:?Compared with wild type mice,iron overload was observed in the brains of P301S mice.LA treatment changed the distribution of iron without affecting the iron levels of P301S mice brain and serum.The involved mechanisms include decreased expression of transferrin receptor(TFR)and increased expression of ferroportin 1(Fpn1).? High-dose LA treatment significantly reduced ROS levels by promoting the expression of antioxidant enzymes,such as SOD1,glutathione peroxidase 4(GPx4)and Cysteine-glutamate antiporter(xCT),as well as the SOD1 activity,reducing calcium content in P301S mice brain,thereby significantly ameliorating the oxidative stress in P301S mice brain.At the same time,high-dose LA treatment also inhibited inflammation reaction in P301S mice brain by decreasing the expression of GFAP,Tumor necrosis factor ?(TNF?)and Interleukin-1?(IL-1?).?High-dose LA significantly inhibited the hyperphosphorylation of Tau protein at AD-related sites Ser202,Ser396,Ser404,Ser416 and Thr181by upregulating the expression of p-GSK3?(Ser9)and PP2A,inhibiting the expression of p-P38,calpain1,p-CDK5 and P25.? High-dose LA inhibited the loss of synapses and neurons mainly through a caspase-dependent manner.However,no significant effect on the autophagy-related proteins was observed.? Morris water maze(MWM),Open field test(OFT)and Novel object recognition test(NOR)showed that LA effectively improved the performance of P301S mice on learning and spatial cognitive ability,and has the potential to relieve anxiety.In summary,LA supplementation effectively changed the distribution of iron in P301S mice brains,alleviated mitochondrial dysfunction and calcium overload,reduced the hyperphosphorylation of Tau at several AD-related sites by inhibiting calpain1 activity,which was associated with the activity relugation of various kinases and phosphatase,alleviated Tau-induced neurodegenerative lesion,and then ameliorated the cognitive decline in P301S transgenic mice.Interestingly,Tau-induced iron overload,lipid peroxidation,and inflammation,which are involved in ferroptosis,were significantly blocked by LA administration,indicating ferroptosis might participate in Tau-induced neurodegeneration.These results provide compelling evidence for the application of LA on the prevention and treatment of tauopathies,including AD.