The Role And Mechnism Of MicroRNA-124/PTPN1 Pathway In Tauopathy Of Alzheimer's Disease

Background: Alzheimer's disease(AD)is the main cause of dementia and one of the great health-care challenges of the 21 st century.In December,2013,the G8 stated that dementia should be made a global priority and their ambition that a cure or a disease-modifying therapy should be available by 2025.Research since the discoveries of ?-Amyloid(A?)and microtubule-associated protein tau(tau),the main components of plaques and tangles respectively,has provided detailed information about molecular pathogenetic events of AD,yet little is known about the cause of Alzheimer's disease and no curative treatments are available.Tau belongs to the family of microtubule-associated proteins and is a highly soluble,naturally unfolded protein whose function is to stabilize the microtubule structure and promote its aggregation.In AD,the lesions are characterized by(1)hyperphosphorylation of tau protein;(2)tau protein aggregates in neurons and glial cells into insoluble fibrils;(3)tau protein redistributes from axon to dendrite.This article discusses the effects of the mi R-124/PTPN1 pathway on tau lesions in these three aspects.A number of studies have shown that Micro RNAs(mi RNAs)are closely related to Alzheimer's disease.Studies have reported that elevated levels of micro RNA-124(mi R-124)are detected in the prefrontal cortex of patients with AD,and the known tau selective splicing inhibitor,tyrosine protein phosphatase non-receptor type 1(PTPN1),serves as its target.Our previous studies demonstrated that A? induced increased expression of mi R-124 in the brain of Tg2576 mice.mi R-124 directly targets the 3'-UTR of PTPN1 to inhibit its translation,thereby damaging the ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor(AMPAR)signaling pathway and destroying Synaptic transmission,synaptic plasticity and memory function.The above results suggest that the tau lesions in AD may through mi R-124/PTPN1 pathway.Objective: The mechanism of the effects of mi R-124/PTPN1 on tau lesions in AD is unknown,so we explore its molecular mechanism.Methods: The expression of mi R-124 was detected by RT-PCR in 10-month-old P301 S mutant mice.The expression of PTPN1 and the phosphorylation level of tau protein at the AD-related site were detected by Western blotting.Inject mi R-124 agonist or PTPN1 interfering virus into 6-month-old C57Bl/6 wild-type adult mice,or inject mi R-124 antagonist or PTPN1 overexpressing virus in 10-month-old P301 S mutant mice by stereotactic injection of mouse brain.Changes in tau protein phosphorylation levels at AD-related sites were detected by Western blot and immunohistochemistry.The soluble tau protein and the insoluble tau protein were separated by 70% formic acid extraction,and the change of tau protein phosphorylation level at the AD-related site was also detected by Western blotting.Immunohistochemical methods also detect alterations in the location of tau protein in the hippocampal CA3 region.Changes in learning and memory and emotional-related behavior were examined through behavioral experiments(including Morris water maze,conditional fear test,and elevated plus maze).Finally,Western blotting was used to detect the changes of Glycogen synthase kinase 3 beta(GSK-3?)and protein phosphatase 2A(PP2A)in the above mice.Results: 1.Mi R-124 was up-regulated,PTPN1 was down-regulated,and there was hyperphosphorylation of tau protein in 10 month old P301 S mutant mice.2.Overexpression of mi R-124 or inhibition of PTPN1 in 6-month-old C57B1/6 wild-type adult mice promotes hyperphosphorylation of tau protein,which occurs in insoluble tau,and stimulates tau protein to shift from axon to the dendrite.3.Overexpression of mi R-124 or inhibition of PTPN1 in 6-month-old C57B1/6 wild-type adult mice,behavioral tests further confirmed that their learning and memory abilities were also damaged.4.Inhibited mi R-124 or overexpressed PTPN1 in 10-month-old P301 S mutant mice,reversal of tau protein hyperphosphorylation is also proved to be reversal of insoluble tau protein hyperphosphorylation.The pathological manifestation of tau protein shift from axon to dendrite is also reversed.The same behavioral tests further confirmed that their learning and memory skills were improved.5.Mi R-124/PTPN1 may cause AD-like tauopathy by affecting the activity of GSK-3? and PP2 A.Conclusion: This study confirmed in vivo that mi R-124/PTPN1 participates in tauopathy in Alzheimer's disease.Changes in the activity of GSK-3? and PP2 A may mediate this pathological process.