| Alzheimer’s disease(AD)is a progressive disease associated with memory loss and impaired cognitive function that affects millions of people worldwide and poses a substantial financial burden.Its pathological features include amyloid plaque deposition resulted from oligopolymeric peptides of amyloid β protein(Aβ),hyperphosphorylation of of Tau protein and aggregation,causing neurofibrillary tangles(NFTs),and neuronal death.However,so far,the cause and mechanism of AD are not clear,and there is no ideal treatment.Therefore,understanding the underlying molecular mechanism is of great significance for the diagnosis and treatment of AD.Glutamate is the most abundant excitatory neurotransmitter in the mammalian central nervous system,and its receptors,especially N-methyl-d-aspartate(NMDA)receptor,are essential for synaptic plasticity and survival of neurons.According to their distribution,NMDA receptor is divided to synaptic NMDA receptor(sNMDAR)and extrasynaptic NMDA receptor(eNMDAR).sNMDAR is distributed in the postsynaptic membrane and is activated when glutamate concentration in the synaptic cleft increases,mediating synaptic transmission and synaptic plasticity.eNMDAR is distributed in the perisynaptic region and is activated only when glutamate concentrations in the synaptic cleft are excessively elevated and spill out of the synapse,and activation of this receptor usually mediates excitotoxic effects that cause neuronal damage.Studies have shown that Aβ deposition in AD can induce abnormal activation of eNMDAR and abnormal internalization of sNMDAR,which in turn causes synaptic damage and loss,and aggravates the occurrence and development of cognitive impairment in AD.Striatal-enriched protein tyrosine phosphatase 61(STEP61)is involved in the activation of different downstream signaling pathways caused by abnormal activation of eNMDAR and abnormal internalization of sNMDAR.STEP61 is a nervous system-specific tyrosine phosphatase,which causes dephosphorylation of substrates and reduces their activity.The substrate of STEP61 includes NMDA receptor,ERK1/2 and p38 MAPK of the MAPKs family.Especially,STEP61 can interact with eNMDAR.When eNMDAR is abnormally activated,the degradation of STEP61 mediated by m-calpain increases and activity of STEP61 decreases.These changes increase the phosphorylation of its substrate p38 MAPK and eNMDAR at the GluN2B-Tyr1472 site.The phosphorylation of eNMDAR GluN2B promotes its expression on the cell membrane and further intensifies the degradation of STEP61.These form a vicious cycle that eventually leads to neuronal damage and exacerbates cognitive impairment.Aβ peptide can upregulate the expression and activity of STEP61 in the synaptic region through different mechanisms,resulting in excessive internalization of sNMDAR and impairing synaptic transmission,promoting the occurrence and development of cognitive impairment.Since eNMDAR can only be activated when glutamate concentration increases in the synaptic cleft,spills over into the perisynaptic region,or when glial cells release glutamate to the perisynaptic region,the balance of glutamate concentration in the perisynaptic region is critical for eNMDAR activation.The balance of glutamate in the synaptic cleft and its surrounding regions is mainly dependent on the uptake of glutamate by excitatory amino acid transporters(EAATs).Among them,EAAT2,also known as glutamate transporter-1(GLT-1),is mainly expressed in the astrocytes of the brain,removes 70-80%of glutamate in the synaptic cleft,and then plays a crucial role in maintenance of the homeostasis of glutamate concentration.A large number of studies have shown that significant GLT-1 damage occurs in AD,causing glutamate to spill out and activate eNMDAR,leading to neuronal damage and synaptic plasticity damage.Therefore,restoring the GLT-1 impairment may be a target for blocking eNMDAR activation to improve cognitive dysfunction in AD.Ceftriaxone(Cef)is a β-lactam antibiotic.Rothstein et al.reported in Nature that Cef specifically increases GLT-1 expression and its uptake of glutamate.Because of this property,Cef has been used in the study of a variety of neurodegenerative diseases associated with elevated glutamate levels,including cerebral ischemia,amyotrophic lateral sclerosis,and epilepsy.Our previous study showed that ceftriaxone upregulates GLT-1 expression in APP/PS1 AD mice in the early stages,enhances their glutamate uptake,reduces extracellular glutamate concentration,and improves cognitive impairment.Recent studies have found that Cef can also significantly reduce amyloid deposition,neuroinflammatory response,and improve cognitive impairment caused by Aβ neurotoxicity.Therefore,we hypothesize that Cef can potentially reduce abnormal eNMDAR activation and internalization of sNMDAR in AD by upregulating GLT-1 expression and function and reducing amyloid deposition,ultimately improving synaptic plasticity impairment and cognitive dysfunction in AD.In order to confirm the hypothesis,this study investigates the improvement effect of Cef on synaptic plasticity damage and cognitive impairment in APP/PS1 AD model mice,and explores its mechanism in the aspects of eNMDAR-S TEP61 signaling expression and activation and synaptic STEP61-mediated sNMDAR expressional changes.The study would provide a new clue and target for the clinical study using β-lactam drugs such as Cef to prevent and treat AD.Part I Cef improves the expression and activation of eNMDAR-STEP61 signaling in APP/PS1 AD model miceObjective:As a downstream signal of eNMDAR,STEP61 can interact with eNMDAR.On the one hand,the activation of eNMDAR promotes m-calpain-mediated cleavage of STEP61,resulting in downregulation of STEP61 expression and activity,which increases phosphorylation and activity of p38 MAPK,leading to neuronal damage.On the other hand,downregulation of STEP61 expression and activity resulted from the activation of eNMDAR can enhance the phosphorylation of GluN2B-Tyr1472 site by decreasing its dephosphorylation,resulting in increased eNMDAR expression on cell membranes.These interactions thus form a vicious circle and promote the development of AD.Therefore,this part studies the effect of Cef on the expression of eNMDAR and its downstream signals,including STEP61 and p38 MAPK,as well as the effect of regulating STEP61 on the above Cef effects,to explore the role of the eNMDAR-STEP61 signaling in Cef-induced improvement on cognitive impairment in APP/PS1 AD model mice.Methods:1.Effects of Cef on the expression and activation of eNMDAR-STEP61 signaling in APP/PS1 AD model miceC57BL/6J wild-type mice and APP/PS1 AD model mice were used.The grouping and treatments for each group are as follows(5 animals were included in each group):(1)wild-type(WT)group:C57BL/6J wild-type mice,no treatment.(2)APP/PS1 group:APP/PS1 AD model mice were injected intraperitoneally with normal saline(as a solvent control),and the injection dose and injection time were the same as those in the APP/PS1+Cef group.(3)APP/PS1+Cef group:APP/PS1 AD model mice were intraperitoneally injected with Cef solution(200 mg/kg)dissolved in normal saline,once a day for 14 consecutive days.The hippocampus of the mice was separated under isoflurane anesthesia within 24 hours after the completion of treatments,and extrasynaptic components of the hippocampal homogenate were separated by density differential centrifugation.Western blot was used to detect the expression of extrasynaptic GluN2B,GluN2BTyr1472,m-calpain,STEP61,STEP33,phosphorylated p38 MAPK and p38 MAPK.2.Effect of modulation STEP61 on the effect of Cef on eNMDAR and related pathways in APP/PS1 AD model miceAAV-STEP61 and AAV-STEP61-shRNA were used to upregulate or downregulateSTEP61 expression,respectively,in APP/PS1 AD model mice.The grouping and treatments for each group are as follows(5 animals were included in each group):(1)wild-type(WT)group:C57BL/6J wild-type mice,no treatment.(2)APP/PS1 group:APP/PS1 AD model mice were injected intraperitoneally with normal saline(as a solvent control),and the injection dose and injection time were the same as those in the APP/PS 1+Cef group.(3)APP/PS 1+Cef group:APP/PS 1 AD model mice were intraperitoneally injected with Cef solution(200 mg/kg)configured with normal saline,once a day for 14 consecutive days.(4)APP/PS1+STEP61 group:APP/PS1 AD model mice were injected with AAV-STEP61 into the lateral cerebral ventricles,2 μL/side.After a recovery for two weeks,the mice were intraperitoneally injected with normal saline in the same protocol to that in the APP/PS 1+Cef group.(5)APP/PS1+STEP61+Cef group:APP/PS 1 AD model mice were injected with AAV-STEP61 into the lateral cerebral ventricles,2 μL/side.After a recovery for two weeks,the mice were intraperitoneally injected with Cef solution(200 mg/kg)dissolved in normal saline,once a day for 14 continuous days.(6)APP/PS1+shSTEP61 group:APP/PS1 AD model mice were injected with AAV-STEP61-shRNA into the lateral cerebral ventricles,2 μL/side.After a recovery for two weeks,the mice were intraperitoneally injected with normal saline in the same protocol to that in the APP/PS 1+Cef group.(7)APP/PS1+shSTEP61+Cef group:APP/PS1 AD model mice were injected with AAV-STEP61-shRNA into the lateral cerebral ventricles,2μL/side.After a recovery for two weeks,the mice were intraperitoneally injected with Cef solution(200 mg/kg)dissolved in normal saline,once a day for 14 continuous daysThe hippocampus of the mice was separated under isoflurane anesthesia within 24 hours after the completion of treatments,and extrasynaptic components of the hippocampal homogenate were separated by density differential centrifugation.Western blot was used to detect the expression of extrasynaptic GluN2B,GluN2BTyr1472,phosphorylated p38 MAPK and p38 MAPK.Results:1.Cef reduced the expression and activation of eNMDAR-STEP61 signaling in APP/PS1 AD model miceWestern blot results showed that compared with the wild-type group,the expression of extrasynaptic GluN2B and m-calpain was increased,the expression of STEP61 decreased,and the expression of STEP33,GluN2BTyr1472 and phosphorylated p38 MAPK was increased in the APP/PS1 group(P<0.05).After Cef treatment(APP/PS1+Cef group),the expression of extrasynaptic GluN2B and m-calpain decreased,the expression of STEP61 increased,the expression of STEP33,GluN2BTyr1472 and phosphorylated p38 MAPK decreased compared with the APP/PS1 group(P<0.05).There was no significant difference in p38 MAPK expression in each group(P>0.05).2.Modulation STEP61 affected the improving effect of Cef on eNMDAR and related signaling in APP/PS1 AD model mice2.1 Changes in the expressions of extrasynaptic GluN2B and GluN2BTyr1472The Western blot results showed that compared with APP/PS1,the expression of extrasynaptic GluN2B,in the APP/PS1+STEP61 group was reduced(P<0.05).Compared with the APP/PS1+Cef treatment group,the expression of extrasynaptic GluN2B in the APP/PSl+STEP61+Cef group was further reduced(P<0.05).In contrast to STEP61 overexpression,the expression of extrasynaptic GluN2B was increased by down-regulating STEP61 expression in APP/PS1 AD mice,which showed that the expression of extrasynaptic GluN2B in the APP/PS1+shSTEP61 group was upregulated compared with the APP/PS1 group(P<0.05).Moreover,AAV-STEP61-shRNA also reduced the inhibitory effect of Cef on extrasynaptic GluN2B expression,which was manifested as a significant upregulation of extrasynaptic GluN2B expression in the APP/PS1+shSTEP61+Cef group compared with the APP/PS1+Cef group(P<0.05)The effect of modulation STEP61 on the expression of extrasynaptic GluN2BTyr1472 was similar to that of extrasynaptic GluN2B in each group.2.1 Changes in the expressions of extrasynaptic p38 MAPKThe Western blot results showed that the expression of extrasynaptic phosphorylated p38 MAPK in APP/PS1+STEP61 mice was lower than that in the APP/PS1 AD mice(P<0.05).After Cef treatment,the expression of extrasynaptic phosphorylated p38 MAPK in the APP/PS1+STEP61+Cef mice was further decreased compared to that in the APP/PS1+Cef mice(P<0.05).In contrast to STEP61 overexpression,the expression of extrasynaptic phosphorylated p38 MAPK increased in APP/PS1+shSTEP61 mice compared to APP/PS1 AD mice(P<0.05).AAV-STEP61-shRNA also reduced the inhibitory effect of Cef on the expression of extrasynaptic phosphorylated p38 MAPK,which was manifested by the significantly upregulation of the expression of extrasynaptic phosphorylated p38 MAPK in the APP/PS1+shSTEP61+Cef group compared with the APP/PS1+Cef group(P<0.05)Modulation of STEP61 had no significant effect on the expression of extrasynaptic p38 MAPK in each group(P>0.05).Summary:1.Cef inhibited the expression and activation of hippocampal eNMDAR-STEP61 signaling in APP/PS1 AD model mice;2.STEP61 upregulation enhanced the inhibitory effect of Cef on the expression of eNMDAR and reduced the activation of p38 MAPK in APP/PS1 AD model mice;3.STEP61 downregulation decreased the inhibitory effect of Cef on the expression of eNMDAR and reduces the activation of p38 MAPK in APP/PS1 AD model mice.Part Ⅱ Cef improves the abnormality in expression and activation of sNMDAR and synaptic STEP61 in APP/PS1 AD model miceObjective:Amyloid β protein(Aβ)deposition is one of the hallmarks of AD,which can promote sNMDAR internalization by upregulating STEP61 expression,reduce ERK1/2 phosphorylation level,aggravate synaptic loss and synaptic plasticity damage during AD,and aggravate cognitive impairment.Studies have found that Cef can reduce the deposition of Aβ and improve cognitive impairment caused by Aβ neurotoxicity.Therefore,this part studies the effects of Cef on the expression of sNMDAR,synaptic STEP61 and ERK1/2,as well as the effect of regulating STEP61 on the above Cef effect,and explores whether by improving the expression and activation of sNMDAR and synaptic STEP61,Cef play a role in improving cognitive impairment in APP/PS1 AD model mice.Methods:1.Effects of Cef on sNMDAR and synaptic STEP61 expression and activation in APP/PS1 AD model miceThe experimental animals and groups used are the same as Part Ⅰ.1.The synaptic components of hippocampal tissues were separated by density differential centrifugation.Western blot was used to detect the expressions of STEP61,PSD95,GluN2B,GluN2BTyr1472,phosphorylated ERK1/2 and ERK1/2 in the hippocampal synaptic region of each group of mice.2.Effect of modulation STEP61 on the expression and activation effect of Cef on changing sNMDAR and related pathways in APP/PS1 AD model miceAAV-STEP61 was used to upregulated,and AAV-STEP61-shRNA was used to downregulated STEP61 expression.The experimental animals,grouping and treatments in each group were the same as those in Part I.2.The synaptic components of hippocampal tissues were separated by density differential centrifugation.Results:1.Cef increased the expression of sNMDAR,PSD95 and phosphorylated ERK1/2 and decreased the expression of synaptic STEP61 in APP/PS1 AD model miceWestern blot results showed that compared with the wild-type group,the expression of GluN2BTyr1472,GluN2B,PSD95 and phosphorylated ERK1/2 was decreased,while the expression of STEP61 was increased in the hippocampal synaptic region of in the APP/PS1 group(P<0.05).After Cef treatment(APP/PS1+Cef group),the expression of GluN2BTyr1472,GluN2B,PSD95 and phosphorylated ERK1/2 was increased,and the expression of STEP61 was decreased(P<0.05).There was no significant difference in ERK1/2 expression between groups(P>0.05).2.Modulation of STEP61 affected the effect of Cef on improving sNMDAR expression and related signals in APP/PS1 AD model mice2.1 Changes in the expressions of synaptic GluN2B and GluN2BTyr1472Western blot results showed that compared with APP/PS1 group,the expression of GluN2B was reduced in the hippocampal synaptic region of the APP/PS1+STEP61 group(P<0.05).Compared with the APP/PS1+Cef group,the expression of GluN2B was further reduced in the APP/PS1+STEP61+Cef group(P<0.05).Compared with APP/PS1 group,the expression of GluN2B was increased in the hippocampal synaptic region of the APP/PS1+shSTEP61 group(P<0.05).Compared with the APP/PS1+Cef group,the expression of GluN2B was further increased in the APP/PS1+shSTEP61+Cef group(P<0.05)The effect of modulation of STEP61 on the expression of synaptic GluN2BTyr1472 between groups was similar to that of synaptic GluN2B.2.2 Changes in the expressions of synaptic ERK1/2Western blot results showed that compared with the APP/PS1 group,the expression of synaptic phosphorylated ERK1/2 in the hippocampus was reduced(P<0.05)in the APP/PS 1+STEP61 group.Compared with the APP/PS1+Cef group,the expression of synaptic phosphorylated ERK1/2 was further reduced in the APP/PS1+STEP61+Cef group(P<0.05).In contrast to the upregulation of STEP61 expression,synaptic phosphorylated ERK1/2 expression increased after downregulation of STEP61,either with(APP/PS1+Cef+shSTEP61 group vs APP/PS1+Cef group,P<0.05)or without Cef treatment(APP/PS1+shSTEP61 group vs APP/PS1 group,P<0.05).Modulation of STEP61 had no significant effect on the expression of synaptic ERK1/2 between groups(P>0.05).Summary:1.Cef enhanced the expression of sNMDAR,PSD95 and phosphorylated ERK1/2 in APP/PS1 AD model mice,and attenuated the expression and activation of synaptic STEP61 in APP/PS1 AD model mice.2.STEP61 upregulation inhibited,while STEP61 downregulation enhanced the promotion of Cef on the expression of sNMDAR and synaptic activation ERK1/2 in APP/PS1 AD model mice.Part Ⅲ STEP61 modulation affected the improving effect of Cef on synaptic plasticity damage and cognitive impairment in APP/PS1 AD model miceObjective:Based on the research in the first and second parts,this part studies the effect of modulation STEP61 on the improvement of Cef on synaptic plasticity injury and cognitive impairment in APP/PS1 AD model mice,in order to elucidate the role of Cef improving the abnormalities of synaptic and extrasynaptic NMDA receptor and STEP61 signaling pathways in improving cognitive impairments of AD.Methods:1.Effect of STEP61 modulation on the improving effect of Cef on synaptic plasticity damages in APP/PS1 AD model miceThe experimental animals,grouping and treatments in each group were the same as those in Part I.2.The following tests were performed within 24 hours after the completion of treatments in each group:(1)Synaptic structural plasticity:Dendritic spine density and dendritic bead-like changes were examined using Golgi staining.(2)Synaptic transmission plasticity:Long-term potentiation(LTP)of the hippocampal Schaffer collaterals-CA1(SC-CA1)pathway was examined using electrophysiological approaching.2.Effect of STEP61 modulation on the improving effect of Cef on cognitive impairments in APP/PS1 AD model miceThe experimental animals,grouping and treatments in each group were the same as those in Part I.2.The following tests were performed after the completion of relative treatments:(1)Novel object recognition(NOR)and novel position recognition(NPR)tests:The tests were performed on the 8th day of injection of Cef,persisting a total of 3 days.Cef was given continuously during testing.(2)Morris water maze(MWM)test:The test was performed on the 11th day of injection of Cef,for a total of 4 days.Cef was given continuously during testing.Results:1.The modulation of STEP61 affected the improving effect of Cef on synaptic plasticity damages in APP/PS1 AD model mice1.1 Changes in dendritic spine density and dendritic beading densityGolgi staining showed similar trend in changes in dendritic spine density and dendritic beading in the CA1,CA3 and DG regions of the hippocampus.The dendritic spine density was reduced and the dendritic beading increased in the APP/PS1 group compared with the wild-type group(P<0.05).After Cef treatment(APP/PS1+Cef group),dendritic spine density increased and dendritic beading decreased compared with APP/PS1 group(P<0.05).STEP61 upregulation in APP/PS1 mice(APP/PS1+STEP61 group)further reduced dendritic spine density,and increased dendritic beading compared with APP/PS1 group(P<0.05).Notably,STEP61 upregulation inhibited the improving effect of Cef on the changes in dendritic spine density dendritic beading,represented with reduction of the dendritic spine density and increase of dendritic beading in the APP/PS1+STEP61+Cef group compared with the APP/PS1+Cef group(P<0.05).After STEP61 downregulation(APP/PS1+shSTEP61 group),dendritic spine density increased and dendritic beading decreased compared with APP/PS1 group(P<0.05).Furthermore,compared with the APP/PS1+Cef group,the dendritic spine density was increased and the dendritic beading were reduced in the APP/PS1+shSTEP61+Cef group(P<0.05).1.2 Changes in long-term potentiationThere was no significant difference in input-output response and paired-pulse facilitation between the groups.LTP impairment in the APP/PS1 group was manifested by reduction in the slope of fEPSP compared with the wild-type group(P<0.05).Cef treatment significantly reduced the LTP damage in the APP/PS1 group,which was manifested by a significant increase in the slope of fEPSP in the APP/PS1+Cef group compared with the APP/PS1 group(P<0.05).STEP61 upregulation in APP/PS1 mice did not significantly aggravate the LTP damage in APP/PS1 AD mice,but effectively inhibited the mitigating effect of Cef on damaged LTP in APP/PS1 AD mice,which showed that the slope of fEPSP decreased in the APP/PS1+STEP61+Cef group compared with the APP/PS1+Cef group(P<0.05).In contrast to STEP61 upregulation,STEP61 downregulation significantly improved the LTP damage of APP/PS1 AD mice,which was shown by that the slope of fEPSP in the APP/PS1+shSTEP61 group increased significantly compared with the APP/PS1 group(P<0.05).It is worth noting that the treatment of AAV-shSTEP61 further enhanced the improvement effect of Cef on impaired LTP in APP/PS1 AD mice,which can be demonstrated by the large increase in the slope of fEPSP in the APP/PS1+shSTEP61+Cef group compared with the APP/PS1+Cef group(P<0.05).2.The modulation of STEP61 affected the improving effect of Cef on cognitive impairments in APP/PS1 AD model mice2.1 Changes in novel object recognition and Novel place recognition testsThe APP/PS 1 mice significantly reduced the recognition indices(RI)of NOR and NPR compared with the wild-type group(P<0.05).Cef(APP/PS1+Cef group)significantly increased the RI of NOR and NPR compared with the APP/PS 1 group(P<0.05).STEP61 upregulation in APP/PS1 mice(APP/PS1+STEP61 group)reduced,while STEP61 downregulation(APP/PS1+shSTEP61 group)increased the RI of NOR and NPR compared with APP/PS1 mice(P<0.05).In particular,STEP61 modulation significantly affected the improvement of Cef on NOR and NPR tests in APP/PS1 AD mice,which was manifested as a significant decrease,while a significant increase in the RI of NOR and NPR in the APP/PS1+STEP61+Cef group and the APP/PS1+shSTEP61+Cef group,respectively,compared with the APP/PS1+Cef group(P<0.05).2.2 Changes in Morris water maze testIn the positioning navigation trials,the escape latency of the APP/PS 1 group mice was significantly longer than that of wild-type mice(P<0.05).Cef(APP/PS1+Cef group)significantly shortened the escape latency compared with the APP/PS 1 group(P<0.05).STEP61 upregulation in APP/PS1 mice(APP/PS1+STEP61 group)further increased the escape latency compared with APP/PS 1 group(P<0.05),while STEP61 downregulation in APP/PS1 mice shortened the escape latency(P<0.05).In particular,STEP61 modulation significantly affected the improvement of Cef on the escape latency in APP/PS1 AD mice,which was manifested by an increase and a decrease in the escape latency in the APP/PS1+STEP61+Cef and APP/PS1+shSTEP61+Cef groups,respectively,compared with the APP/PS1+Cef group(P<0.05).In the spatial exploration trials,the target quadrant residence time and the number of crossing platform in APP/PS1 AD mice were significantly reduced compared with the wild-type group(P<0.05).The Cef treatment(APP/PS1+Cef group)significantly increased the target quadrant residence time and the number of crossing platform compared with the APP/PS1 group(P<0.05).STEP61 upregulation in APP/PS1 mice(APP/PS1+STEP61 group)further reduced,while STEP61 downregulation(APP/PS1+shSTEP61 group)increased the target quadrant residence time and the number of crossing platform compared with the APP/PS1 group(P<0.05).STEP61 modulation also significantly affected the improvement of Cef on the time of target quadrant retention and the number of crossing platform in APP/PS1 AD mice,which was shown by that compared with the APP/PS1+Cef group,the target quadrant residence time and the number of crossing platform were significantly reduced in the APP/PS1+STEP61+Cef group,while they were increased in the APP/PS1+shSTEP61+Cef group(P<0.05).Summary:STEP61 upregulation inhibited,while STEP61 downregulation enhanced the improving effect of Cef on synaptic structure and transmission plasticity damages and cognitive impairments in APP/PS1 AD model mice.Conclusion1.Cef inhibited the expression and activation of eNMDAR-STEP61 signaling in APP/PS1 AD model mice.2.Cef enhanced the expression of sNMDAR in APP/PS1 AD model mice and downregulated the expression and activation of synaptic STEP61.3.STEP61 upregulation of enhanced the inhibitory effect of Cef on eNMDAR and related signals,while inhibited the improving effect of Cef on sNMDAR and related signals and synaptic plasticity damage and cognitive impairments in APP/PS1 AD model mice.4.STEP61 downregulation weakened the inhibitory effect of Cef on eNMDAR and related signals,while enhanced the improving effect of Cef on sNMDAR and related signals,and synaptic plasticity damage and cognitive impairments in APP/PS1 AD model mice.The above findings suggested that Cef can improve synaptic plasticity impairment and cognitive deficits in APP/PS1 AD model mice by regulating NMDAR-STEP61 signaling. |
PDF Full Text Request