MiR-128 Induces Neurodegeneration In Alzheimer's Disease By Targeting STIM2

Background:Alzheimer's disease(AD)is the most common cause of brain degeneration characterized by a progressive memory decline.And recent studies indicate that memory loss is caused by synaptic dysfunction rather than neuronal death.Micro RNAs(mi RNAs)belong to a class of highly conserved small non-coding RNAs that interfere with target gene expression by binding to the 3'-UTR of their target m RNAs.With the development of sequencing technology,mi RNAs are not only involved in the pathogenesis of AD,but also played an important role in the diagnosis and treatment of AD.Our group previously found that dentate gyrus mossy cells(MCs)control memory precision via directly and functionally innervating local somatostatin(SST)inhibitory interneurons.However,it is not clear how the content of synaptic transmission changes between dentate gyrus MCs and SST cells,whether it affects memory precision in AD model mice,and the specific mechanism of memory imprecision.Objectives:To determine whether the neural circuit between dentate gyrus MCs and SST cells is abnormal in AD model mice,and investigate the specific molecular mechanisms of their abnormalities,and warrants a promising target for therapeutic intervention of memory decays in the early stage of AD.Methods:In AD mice at 3,6,8,or 10 months old of age,a series of behavioral tests were conducted to explore the related functions of memory imprecision in behavior.MCs were specifically labeled and identified by constructing AD/Calb2^Cre+SST^FLP+mutant mice combined with Cre recombinase-dependent virus injection.By using whole-cell patch-clampcombined with optogenetics,the mechanismof memory imprecision was investigated.With the method of single cell RNA sequencing and luciferase reporter system,the key molecule of memory imprecision was detected.Furthermore,by infecting virus and intravenous injecting a locked nucleic acid(LNA)modified oligonucleotide,the silencing mi R-128 or uncoupling mi R-128 binding to STIM2,and/or expressing exogenous STIM2 with MCs were investigated.Following the whole-cell patch-clamp combined behavioral tests,we verified the specific mechanism of the memory imprecision in behavior.Results:Memory imprecision is found in 6-month-old AD mice.6-month-old AD/Calb2^Cre+SST^FLP mutant mice were treated with r AAV1/2-DIO-GFP and r AAV1/2-f DIO-td Tomato viruses.Furthermore,MCs and SST cells of mutant mice were specifically labeled and identified combined with optogenetics and whole-cell patch-clamp technology,we identified the mechanism of memory imprecision is caused by the dysfunction of synaptic transmission between dentate gyrus MCs and SST cells.Single cell RNA sequencing reveals that mi R-128 that binds to a 3'UTR of STIM2 and inhibits STIM2 translation is increasingly expressed in MCs from AD mice at early.Silencing mi R-128 or disrupting mi R-128 binding to STIM2 evokes STIM2 expression,restores synaptic function and rescues memory imprecision in AD mice.Comparable findings are achieved by directly engineering MCs with the expression of STIM2.Conclusions:1.Memory imprecision is caused by the dysfunctional long-term potentiation(LTP)ofsynaptic transmission between dentate gyrus MCs and SST cells in a mouse modelof early AD.2.MiR-128,which binds to a 3'UTR-region of STIM2 and inhibits STIM2translation,is increasingly expressed in MCs from in an early stage of AD mice.3.Silencing mi R-128 or uncoupling mi R-128 binding to STIM2,and/or expressingexogenous STIM2 restores synaptic function of MCs and significantly improvesthe quality of memories in an early stage of AD mice.