| BackgroundAlzheimer's disease(AD)is the most common form of dementia 's disease.The clinical manifestations were progressive memory loss and cognitive dysfunction.Many failures in AD drug development have occurred,with both small molecules and immunotherapies failing to show a drug/placebo difference or having unacceptable toxicity,with an overall success rate during the past ten-year period of 0.4%.There is still no specific drug for AD.Such a high rate of research and development failure may be due to the unclear pathogenesis of AD.All drugs targeting the existing pathogenesis,such as A? antibodies,have failed.A reduction in the number or activity of synaptic NMDARs,further shifting the NMDARs balance,leaded to the disorder of NMDARs signals,synaptic loss,plasticity and cognitive deficits in AD patients.Therefore,targeting pathological changes in AD will improve the specificity of AD treatment.ObjectiveNow,more and more studies indicate synaptic degradation in early stage of AD,and both pathological synaptic degeneration and physiological synaptic number change are closely related to NMDARs-dependent synaptic plasticity.Theoretically,it is possible to facilitate NMDARs-dependent synaptic plasticity and rescue synaptic degeneration in AD by enhancing the function of NMDARs.Therefore,whether NMDAR positive allosteric modulators can improve synaptic plasticity and rescue phenotype of AD memory loss and cognitive dysfunction by activating synaptic NMDA receptors in AD,is expected to advance drug development for the treatment of early AD.MethodsHere,we used computer-aided drug discovery and optimized drug.We used patchclamp to detect whether Npam105 enhanced NMDA receptor function,in-vivo recording to verify whether Npam105 enhanced synaptic plasticity,and enhanced animal learning and memory.Further we detected whether Npam105 can improve AD model mice(5XFAD)synaptic plasticity imbalance(LTP inhibition)and rescue memory loss and cognitive dysfunction.ResultsOur results showed that Npam105 can enhance NMDA receptor current in vitro.Npam105 can facilitate synaptic plasticity(LTP and LTD)in vivo WT animals,in the behavioral results indicate that Npam105 can be used as a cognitive enhancer to enhance the learning and memory.On the other hand,under pathological conditions,Npam105 can rescue the synaptic plasticity imbalance(LTP inhibition)in AD mice,and also improve the learning and memory,rescued cognitive deficits.ConclusionsOur results demonstrated that NMDA receptor function and synaptic plasticity play a crucial role in AD memory loss.NMDAR positive allosteric modulators(Npam105)may be an effective drug for treatment of AD.Background The pyramidal neurons in the EC layer II(ECIIPN)directly innervate CA1 parvalbumin(PV)neurons(CA1PV)and are selectively degenerated in AD mice.And the normal synaptic function is required for leaning and memory.Objective The loss of ECIIPN-CA1 PV synapses disable the excitatory and inhibitory balance in the CA1 circuit.However,there is still no accurate treatment method to prevent synapse damage in early AD.Methods We expressed ChR2(E123A)in ECIIPN via Cre-loxp system,and manipulated the neural activity of pyramidal neurons in the EC layer II region by optogenetics.TBS stimulation pattern was enrolled to against the decay of ECIIPN-CA1 PV synapse and single unit recording was used to evaluate the excitatory and inhibitory balance and the change of local field potentiation(LFP)power in AD Transgenic mice.Results We found that the TBS stimulation attenuates the synaptic decay in ECIIPN-CA1 PV pathway,which further rescue the spatial learning and memory defects in early AD transgenic mice.Conclusions Here,our results not only reveals plasticity-related optical stimulation targeted to rescue the ECIIPN-CA1 PV synaptic loss intercepts spatial learning and memory decline in the AD mice,but also indicated artificial plasticity related stimulation as a promising way for the therapeutic intervention to treat disease progression of AD. |
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