Synaptic dysfunction occurs early in Alzheimer＇s disease （AD） and is acknowledged as a primary pathologic target for treatment. Synaptic degeneration is the pathological feature most strongly correlated with loss o...Synaptic dysfunction occurs early in Alzheimer＇s disease （AD） and is acknowledged as a primary pathologic target for treatment. Synaptic degeneration is the pathological feature most strongly correlated with loss of cognitive function ante mortern （Terry et al., 1991）. Synapses are heavily damaged in hippocampal and neocortical regions of AD brain, whereas motor and occipital cortices are relatively spared （Honer et al., 1992）. Despite extensive work, the molecular mechanisms underlying synaptic degeneration are largely unknown.展开更多
The health benefits of physical exercise are well established and have been observed in both human studies and rodent models[1],improving overall health and stress resilience.However,the underlying molecular mechanism...The health benefits of physical exercise are well established and have been observed in both human studies and rodent models[1],improving overall health and stress resilience.However,the underlying molecular mechanisms have not been comprehensively investigated.Previous studies have focused extensively on its neuromodulatory effects and have also identified multiple exercise-associated molecular substrates and blood-borne metabolites,including neurotrophic factors,monoamine neurotransmitters,neuroinflammatory cytokines,kynurenine,N-lactoylphenylalanine,and the ketone bodyβ-hydroxybutyrate[2].Notably,lactate,a common energy source derived from cellular glycolysis in response to intensive exercise,has recently been reported to exert antidepressant activity[3].However,a detailed mechanistic explanation is lacking.展开更多
Huntington＇s disease （HD） is a neurodegenera- tive disease caused by a polyglutamine expansion in the huntingtin （Htt） protein. Mutant Htt causes synaptic transmission dysfunctions by interfering in the expressio...Huntington＇s disease （HD） is a neurodegenera- tive disease caused by a polyglutamine expansion in the huntingtin （Htt） protein. Mutant Htt causes synaptic transmission dysfunctions by interfering in the expression of synaptic proteins, leading to early HD symptoms. Synaptic vesicle proteins 2 （SV2s）, a family of synaptic vesicle proteins including 3 members, SV2A, SV2B, and SV2C, plays important roles in synaptic physiology. Here, we investigated whether the expression of SV2s is affected by mutant Htt in the brains of HD transgenic （TG） mice and Neuro2a mouse neuroblastoma cells （N2a cells） expressing mutant Htt. Western blot analysis showed that the protein levels of SV2A and SV2B were not signifi- cantly changed in the brains of HD TG mice expressing mutant Htt with 82 glutamine repeats. However, in the TG mouse brain there was a dramatic decrease in the protein level of SV2C, which has a restricted distribution pattern in regions particularly vulnerable in HD. Immunostaining revealed that the immunoreactivity of SV2C was progres- sively weakened in the basal ganglia and hippocampus of TG mice. RT-PCR demonstrated that the mRNA level of SV2C progressively declined in the TG mouse brain without detectable changes in the mRNA levels of SV2A and SV2B, indicating that mutant Htt selectively inhibits the transcriptional expression of SV2C. Furthermore, we found that only SV2C expression was progressively inhibited in N2a cells expressing a mutant Htt containing 120 glutamine repeats. These findings suggest that the synaptic dysfunction in HD results from the mutant Htt- mediated inhibition of SV2C transcriptional expression. These data also imply that the restricted distribution and decreased expression of SV2C contribute to the brain region-selective pathology of HD.展开更多
Cerebral ischemia is a major health risk that requires preventive approaches in addition to drug therapy.Physical exercise enhances neurogenesis and synaptogenesis,and has been widely used for functional rehabilitatio...Cerebral ischemia is a major health risk that requires preventive approaches in addition to drug therapy.Physical exercise enhances neurogenesis and synaptogenesis,and has been widely used for functional rehabilitation after stroke.In this study,we determined whether exercise training before disease onset can alleviate the severity of cerebral ischemia.We also examined the role of exercise-induced circulating factors in these effects.Adult mice were subjected to 14 days of treadmill exercise training before surgery for middle cerebral artery occlusion.We found that this exercise pre-conditioning strategy effectively attenuated brain infarct area,inhibited gliogenesis,protected synaptic proteins,and improved novel object and spatial memory function.Further analysis showed that circulating adiponectin plays a critical role in these preventive effects of exercise.Agonist activation of adiponectin receptors by Adipo Ron mimicked the effects of exercise,while inhibiting receptor activation abolished the exercise effects.In summary,our results suggest a crucial role of circulating adiponectin in the effects of exercise pre-conditioning in protecting against cerebral ischemia and supporting the health benefits of exercise.展开更多
Objective:To investigate the effect of acupuncture onset time and synaptic structure in two different models of depression.Methods:A total of 150 healthy male adult SPF C57BL/6J mice were divided into five time-point ...Objective:To investigate the effect of acupuncture onset time and synaptic structure in two different models of depression.Methods:A total of 150 healthy male adult SPF C57BL/6J mice were divided into five time-point groups:1 h,3 h,6 h,12 h and 24 h.Each time-point group was further divided into three groups:the model,scopolamine and acupuncture groups with 10 rats each.Rats were given forced swimming stimulation(15 min,once)before the intervention.A total of 200 healthy male adult specific pathogen-free(SPF)Sprague-Dawley(SD)rats were divided into 30 normal rats,and 170 modelling ones.A total of 90 rats were successfully modeled,and were randomly divided into three time-point groups:1 h,6 h and 24 h.And each time-point group was further divided into the normal,model,scopolamine,and acupuncture group.Chronic unpredictable mild stress(CUMS)combined with individual feeding was used to establish the depressed rat model.The sucrose preference test(SPT)and open field test(OFT)were used to evaluate the success of the model.There were 10 rats in each group.The acupuncture intervention was performed once for 20 min on"Baihui(GV20)","Yintang(GV29)","Hegu(LI4)",and"Taichong(LR3)"without any other operations for the corresponding animals.Other groups were given corresponding medications.According to different time points,the forced swimming test(FST)was conducted in mice,and the FST and novelty-suppressed feeding test(NSFT)were measured in rats.Monoamine neurotransmitters(NE,DA,DOPAC,5-HT,5-HIAA,HVA)in the prefrontal cortex and hippocampus were detected with high performance liquid chromatography(HPLC).The expression of synapsin I,PSD95,p-mTOR,mTOR,and BDNF in the prefrontal cortex and hippocampus was determined by western blot.Results:At the 1 h time point,compared with the model group,the immobility time was significantly decreased in the acupuncture group(P<0.05).At 3 h,6 h,12 h,and 24 h,compared with the model group,the immobility time was significantly reduced in both scopolamine and acupuncture groups(P<0.05).At the 1 h time point,compared with the normal group,the immobility time of FST and the latency to feed were significantly increased in the model group(P<0.05).Compared with the model group,the immobility time of FST showed a significant reduction in the acupuncture group(P<0.05).At the 6h and 24 h time points,compared with the normal group,the immobility time of FST and the latency to feed were significantly increased in the model group(P<0.05).Compared with the model group,the immobility time of FST was significantly decreased in the scopolamine and acupuncture groups(P<0.05).At the 1 h and 24 h time points,compared with the normal group,the expression levels of 5-HT,5-HIAA,NE,DA,DOPAC,and HVA of the prefrontal cortical and hippocampal tissues were significantly reduced in the model group(P<0.05).At the 1 h and 24 h time points,compared with the model group,the expression levels of synapsin I,PSD95,p-mTOR,and BDNF of the prefrontal cortex were significantly increased in the acupuncture group(P<0.05).At the 1 h and 24 h time points,compared with the normal group,the expression levels of synapsin I,PSD95,p-mTOR,and BDNF of the prefrontal cortex were significantly reduced in the model group(P<0.05).Compared with the model group,the expression levels of synapsin I,PSD95,p-mTOR,and BDNF of the prefrontal cortex were significantly increased in the acupuncture group(P<0.05).At the 1 h and 24 h time points,compared with the normal group,the expression levels of synapsin I,PSD95,p-mTOR,and BDNF of the hippocampal tissues were significantly reduced in the model group(P<0.05).Compared with the model group,the expression levels of synapsin I,PSD95,p-mTOR,and BDNF of the hippocampus were not significantly different in the acupuncture group(P>0.05).Conclusion:Acupuncture may play a rapid antidepressant effect by increasing the expression of synaptic plasticity proteins in the prefrontal cortex.展开更多
Bushen Tiansui decoction is composed of six traditional Chinese medicines：Herba Epimedii,Radix Polygoni multiflori,Plastrum testudinis,Fossilia Ossis Mastodi,Radix Polygalae,and Rhizoma Acorus tatarinowii.Because Bus...Bushen Tiansui decoction is composed of six traditional Chinese medicines：Herba Epimedii,Radix Polygoni multiflori,Plastrum testudinis,Fossilia Ossis Mastodi,Radix Polygalae,and Rhizoma Acorus tatarinowii.Because Bushen Tiansui decoction is effective against amyloid beta（Aβ） toxicity,we hypothesized that it would reduce hippocampal synaptic damage and improve cognitive function in Alzheimer＇s disease.To test this hypothesis,we used a previously established animal model of Alzheimer＇s disease,that is,microinjection of aggregated Aβ25–35 into the bilateral brain ventricles of Sprague-Dawley rats.We found that long-term（28 days） oral administration of Bushen Tiansui decoction（0.563,1.688,and 3.375 g/m L;4 m L/day） prevented synaptic loss in the hippocampus and increased the expression levels of synaptic proteins,including postsynaptic density protein 95,the N-methyl-D-aspartate receptor 2 B subunit,and Shank1.These results suggested that Bushen Tiansui decoction can protect synapses by maintaining the expression of these synaptic proteins.Bushen Tiansui decoction also ameliorated measures reflecting spatial learning and memory deficits that were observed in the Morris water maze（i.e.,increased the number of platform crossings and the amount of time spent in the target quadrant and decreased escape latency） following intraventricular injections of aggregated Aβ25–35 compared with those measures in untreated Aβ_（25–35）-injected rats.Overall,these results provided evidence that further studies on the prevention and treatment of dementia with this traditional Chinese medicine are warranted.展开更多
Regular exercise has been shown to reduce the risk of Alzheimer’s disease(AD).Our previous study showed that the protein aquaporin 4(AQP4),which is specifically expressed on the paravascular processes of astrocytes,i...Regular exercise has been shown to reduce the risk of Alzheimer’s disease(AD).Our previous study showed that the protein aquaporin 4(AQP4),which is specifically expressed on the paravascular processes of astrocytes,is necessary for glymphatic clearance of extracellular amyloid beta(Aβ)from the brain,which can delay the progression of Alzheimer’s disease.However,it is not known whether AQP4-regulated glymphatic clearance of extracellular Aβis involved in beneficial effects of exercise in AD patients.Our results showed that after 2 months of voluntary wheel exercise,APP/PS1 mice that were 3 months old at the start of the intervention exhibited a decrease in Aβburden,glial activation,perivascular AQP4 mislocalization,impaired glymphatic transport,synapse protein loss,and learning and memory defects compared with mice not subjected to the exercise intervention.In contrast,APP/PS1 mice that were 7 months old at the start of the intervention exhibited impaired AQP4 polarity and reduced glymphatic clearance of extracellular Aβ,and the above-mentioned impairments were not alleviated after the 2-month exercise intervention.Compared with age-matched APP/PS1 mice,AQP4 knockout APP/PS1 mice had more serious defects in glymphatic function,Aβplaque deposition,and cognitive impairment,which could not be alleviated after the exercise intervention.These findings suggest that AQP4-dependent glymphatic transport is the neurobiological basis for the beneficial effects of voluntary exercises that protect against the onset of AD.展开更多
The slit diaphragm bridging the neighboring foot pro-cesses functions as a fnal barrier of glomerular capil-lary wall for preventing the leak of plasma proteins into primary urine. It is now accepted that the dysfunct...The slit diaphragm bridging the neighboring foot pro-cesses functions as a fnal barrier of glomerular capil-lary wall for preventing the leak of plasma proteins into primary urine. It is now accepted that the dysfunction of the sit diaphragm contributes to the development of proteinuria in several glomerular diseases. Neph-rin, a gene product of NPHS1, a gene for a congenital nephrotic syndrome of Finnish type, constitutes an ex-tracellular domain of the slit diaphragm. Podocin was identified as a gene product of NPHS2 , a gene for a familial steroid-resistant nephrotic syndrome of French. Podocin binds the cytoplasmic domain of nephrin. After then, CD2 associated protein, NEPH1 and transient re-ceptor potential-6 were also found as crucial molecules of the slit diaphragm. In order to explore other novel molecules contributing to the development of protein-uria, we performed a subtraction hybridization assay with a normal rat glomerular RNA and a glomerular RNA of rats with a puromycin aminonucleoside ne-phropathy, a mimic of a human minimal change type nephrotic syndrome. Then we have found that synaptic vesicle protein 2B, ephrin-B1 and neurexin were already downregulated at the early stage of puromycin aminonucleoside nephropathy, and that these molecules were localized close to nephrin. It is conceivable that these molecules are the slit diaphragm associated molecules, which participate in the regulation of the barrier func-tion. These molecules could be targets to establish a novel therapy for nephrotic syndrome.展开更多
Stroke may cause upper motor neurons lesions, and thus limb spasm may occur. Brain plasticity refers to the brain's ability to change and adapt the environment and experience when the nervous system is damaged. Ac...Stroke may cause upper motor neurons lesions, and thus limb spasm may occur. Brain plasticity refers to the brain's ability to change and adapt the environment and experience when the nervous system is damaged. Acupuncture can relieve the relevant pathological status due to stroke by enhancing brain plasticity. Specifically, acupuncture may finally achieve the balance between excitatory and inhibitory neurotransmitters by inhibiting the expression of neurotransmitter GABA, neurotrophic factor BDNF and proteins related to synaptic plasticity. This article analyzed and summarized that taking advantage of nervous plasticity the acupuncture could regenerate nervous cells and restore the related regulation of the movement by upper motor neurons, so as to relieving limb spasticity. It also summarized the research and application of acupuncture in regulating related signals, providing a systematic thought for the future study on acupuncture in the treatment of stroke induced limb.展开更多
Epilepsy is a common neurological disorder that is primarily treated with antiseizure medications(ASMs).Although dozens of ASMs are available in the clinic,approximately 30%of epileptic patients have medically refract...Epilepsy is a common neurological disorder that is primarily treated with antiseizure medications(ASMs).Although dozens of ASMs are available in the clinic,approximately 30%of epileptic patients have medically refractory seizures;other limitations in most traditional ASMs include poor tolerability and drug-drug interactions.Therefore,there is an urgent need to develop alternative ASMs.Levetiracetam(LEV)is a first-line ASM that is well tolerated,has promising efficacy,and has little drug-drug interaction.Although it is widely accepted that LEV acts through a unique therapeutic target synaptic vesicle protein(SV)2A,the molecular basis of its action remains unknown.Even so,the next-generation SV2A ligands against epilepsy based on the structure of LEV have achieved clinical success.This review highlights the research and development(R&D)process of LEV and its analogs,brivaracetam and padsevonil,to provide ideas and experience for the R&D of novel ASMs.展开更多
Dementia is characterized by synaptic and neuronal dysfunction in disease-specific brain regions.Repeated failure of dementia clinical trials with therapeutic drugs targeting abnormal protein aggregates has caused res...Dementia is characterized by synaptic and neuronal dysfunction in disease-specific brain regions.Repeated failure of dementia clinical trials with therapeutic drugs targeting abnormal protein aggregates has caused researchers to shift their focus to synaptic functions and increased the importance of clinically available imaging for synaptic density and the development of synapse-targeted intervention.Synaptic density imaging with positron emission tomography(PET)tracer enables non-invasive detection of synaptic loss and hence investigates the association with other neuropathological events exemplified by disease-specific abnormal protein accumulation.Many studies have reviewed the progress of synaptic density imaging;however,to our knowledge,there is no article yet that summarizes the research progress of multimodal imaging of synaptic density tracers combined with other dementia biomarkers.Moreover,synaptic function intervention for dementia therapy has not yet been summarized.In this review,first we detail the progress of synaptic density imaging including tracer development and preclinical/clinical application,followed by a discussion of multimodal imaging of synaptic density tracers combined with classic dementia biomarkers in the clinical research stage.Finally,we briefly summarize the synapse-targeted drugs for dementia therapy.展开更多
Synaptic vesicles can undergo several modes of exocytosis,endocytosis,and trafficking within individual synapses,and their fates may be linked to different vesicular protein compositions.Here,we mapped the intrasynapt...Synaptic vesicles can undergo several modes of exocytosis,endocytosis,and trafficking within individual synapses,and their fates may be linked to different vesicular protein compositions.Here,we mapped the intrasynaptic distribution of the synaptic vesicle proteins SV2B and SV2A in glutamatergic synapses of the hippocampus using three-dimensional electron microscopy.SV2B was almost completely absent from docked vesicles and a distinct cluster of vesicles found near the active zone.In contrast,SV2A was found in all domains of the synapse and was slightly enriched near the active zone.SV2B and SV2A were found on the membrane in the peri-active zone,suggesting the recycling from both clusters of vesicles.SV2B knockout mice displayed an increased seizure induction threshold only in a model employing high-frequency stimulation.Our data show that glutamatergic synapses generate molecularly distinct populations of synaptic vesicles and are able to maintain them at steep spatial gradients.The almost complete absence of SV2B from vesicles at the active zone of wildtype mice may explain why SV2A has been found more important for vesicle release.展开更多
基金Financial support was provided by the Alzheimer’s Australia Dementia Research Foundation Scholarship Program(AAR Postgraduate Research Scholarship),Alzheimer’s Association(USA)under grant#RG1-96-005the Judith Jane Mason and Harold Stannett Williams Memorial Foundation+1 种基金The Queensland Brain Bank,part of Australian Brain Bank Networksupported by an NHMRC(Australia)Enabling Grant No.605210
文摘Synaptic dysfunction occurs early in Alzheimer＇s disease （AD） and is acknowledged as a primary pathologic target for treatment. Synaptic degeneration is the pathological feature most strongly correlated with loss of cognitive function ante mortern （Terry et al., 1991）. Synapses are heavily damaged in hippocampal and neocortical regions of AD brain, whereas motor and occipital cortices are relatively spared （Honer et al., 1992）. Despite extensive work, the molecular mechanisms underlying synaptic degeneration are largely unknown.
基金supported by grants from the National Natural Science Foundation of China(32271062 and 82305117)Science and Technology Program of Guangzhou,China(2023A04J0458)+1 种基金Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment of Refractory Chronic Diseases(2023KT15524)the China Postdoctoral Science Foundation(2024M751343).
文摘The health benefits of physical exercise are well established and have been observed in both human studies and rodent models[1],improving overall health and stress resilience.However,the underlying molecular mechanisms have not been comprehensively investigated.Previous studies have focused extensively on its neuromodulatory effects and have also identified multiple exercise-associated molecular substrates and blood-borne metabolites,including neurotrophic factors,monoamine neurotransmitters,neuroinflammatory cytokines,kynurenine,N-lactoylphenylalanine,and the ketone bodyβ-hydroxybutyrate[2].Notably,lactate,a common energy source derived from cellular glycolysis in response to intensive exercise,has recently been reported to exert antidepressant activity[3].However,a detailed mechanistic explanation is lacking.
基金supported by the National Natural Science Foundation of China(81371417)
文摘Huntington＇s disease （HD） is a neurodegenera- tive disease caused by a polyglutamine expansion in the huntingtin （Htt） protein. Mutant Htt causes synaptic transmission dysfunctions by interfering in the expression of synaptic proteins, leading to early HD symptoms. Synaptic vesicle proteins 2 （SV2s）, a family of synaptic vesicle proteins including 3 members, SV2A, SV2B, and SV2C, plays important roles in synaptic physiology. Here, we investigated whether the expression of SV2s is affected by mutant Htt in the brains of HD transgenic （TG） mice and Neuro2a mouse neuroblastoma cells （N2a cells） expressing mutant Htt. Western blot analysis showed that the protein levels of SV2A and SV2B were not signifi- cantly changed in the brains of HD TG mice expressing mutant Htt with 82 glutamine repeats. However, in the TG mouse brain there was a dramatic decrease in the protein level of SV2C, which has a restricted distribution pattern in regions particularly vulnerable in HD. Immunostaining revealed that the immunoreactivity of SV2C was progres- sively weakened in the basal ganglia and hippocampus of TG mice. RT-PCR demonstrated that the mRNA level of SV2C progressively declined in the TG mouse brain without detectable changes in the mRNA levels of SV2A and SV2B, indicating that mutant Htt selectively inhibits the transcriptional expression of SV2C. Furthermore, we found that only SV2C expression was progressively inhibited in N2a cells expressing a mutant Htt containing 120 glutamine repeats. These findings suggest that the synaptic dysfunction in HD results from the mutant Htt- mediated inhibition of SV2C transcriptional expression. These data also imply that the restricted distribution and decreased expression of SV2C contribute to the brain region-selective pathology of HD.
基金supported by STI2030-Major Projects,No.2022ZD0207600(to LZ)the National Natural Science Foundation of China,Nos.32070955(to LZ),U22A20301(to KFS)+3 种基金the Natural Science Foundation of Guangdong Province,No.2021A1515012197(to HO)Guangzhou Core Medical Disciplines Project,No.2021-2023(to HO)Key Research and Development Plan of Ningxia Hui Automomous Region,No.2022BEG01004(to KFS)Science and Technology Program of Guangzhou,China,No.202007030012(to KFS and LZ)。
文摘Cerebral ischemia is a major health risk that requires preventive approaches in addition to drug therapy.Physical exercise enhances neurogenesis and synaptogenesis,and has been widely used for functional rehabilitation after stroke.In this study,we determined whether exercise training before disease onset can alleviate the severity of cerebral ischemia.We also examined the role of exercise-induced circulating factors in these effects.Adult mice were subjected to 14 days of treadmill exercise training before surgery for middle cerebral artery occlusion.We found that this exercise pre-conditioning strategy effectively attenuated brain infarct area,inhibited gliogenesis,protected synaptic proteins,and improved novel object and spatial memory function.Further analysis showed that circulating adiponectin plays a critical role in these preventive effects of exercise.Agonist activation of adiponectin receptors by Adipo Ron mimicked the effects of exercise,while inhibiting receptor activation abolished the exercise effects.In summary,our results suggest a crucial role of circulating adiponectin in the effects of exercise pre-conditioning in protecting against cerebral ischemia and supporting the health benefits of exercise.
基金Supported by the National Natural Science Funds(82074522,U23A20507)Guangzhou Science and Technology Planning Project(202102010247)+1 种基金the Natural Science Foundation of Guangdong Province(2021A1515011464,2019A1515012043)Research Fund for Bajian Talents of Guangdong Provincial Hospital of Chinese Medicine(BJ2022KY10)。
文摘Objective:To investigate the effect of acupuncture onset time and synaptic structure in two different models of depression.Methods:A total of 150 healthy male adult SPF C57BL/6J mice were divided into five time-point groups:1 h,3 h,6 h,12 h and 24 h.Each time-point group was further divided into three groups:the model,scopolamine and acupuncture groups with 10 rats each.Rats were given forced swimming stimulation(15 min,once)before the intervention.A total of 200 healthy male adult specific pathogen-free(SPF)Sprague-Dawley(SD)rats were divided into 30 normal rats,and 170 modelling ones.A total of 90 rats were successfully modeled,and were randomly divided into three time-point groups:1 h,6 h and 24 h.And each time-point group was further divided into the normal,model,scopolamine,and acupuncture group.Chronic unpredictable mild stress(CUMS)combined with individual feeding was used to establish the depressed rat model.The sucrose preference test(SPT)and open field test(OFT)were used to evaluate the success of the model.There were 10 rats in each group.The acupuncture intervention was performed once for 20 min on"Baihui(GV20)","Yintang(GV29)","Hegu(LI4)",and"Taichong(LR3)"without any other operations for the corresponding animals.Other groups were given corresponding medications.According to different time points,the forced swimming test(FST)was conducted in mice,and the FST and novelty-suppressed feeding test(NSFT)were measured in rats.Monoamine neurotransmitters(NE,DA,DOPAC,5-HT,5-HIAA,HVA)in the prefrontal cortex and hippocampus were detected with high performance liquid chromatography(HPLC).The expression of synapsin I,PSD95,p-mTOR,mTOR,and BDNF in the prefrontal cortex and hippocampus was determined by western blot.Results:At the 1 h time point,compared with the model group,the immobility time was significantly decreased in the acupuncture group(P<0.05).At 3 h,6 h,12 h,and 24 h,compared with the model group,the immobility time was significantly reduced in both scopolamine and acupuncture groups(P<0.05).At the 1 h time point,compared with the normal group,the immobility time of FST and the latency to feed were significantly increased in the model group(P<0.05).Compared with the model group,the immobility time of FST showed a significant reduction in the acupuncture group(P<0.05).At the 6h and 24 h time points,compared with the normal group,the immobility time of FST and the latency to feed were significantly increased in the model group(P<0.05).Compared with the model group,the immobility time of FST was significantly decreased in the scopolamine and acupuncture groups(P<0.05).At the 1 h and 24 h time points,compared with the normal group,the expression levels of 5-HT,5-HIAA,NE,DA,DOPAC,and HVA of the prefrontal cortical and hippocampal tissues were significantly reduced in the model group(P<0.05).At the 1 h and 24 h time points,compared with the model group,the expression levels of synapsin I,PSD95,p-mTOR,and BDNF of the prefrontal cortex were significantly increased in the acupuncture group(P<0.05).At the 1 h and 24 h time points,compared with the normal group,the expression levels of synapsin I,PSD95,p-mTOR,and BDNF of the prefrontal cortex were significantly reduced in the model group(P<0.05).Compared with the model group,the expression levels of synapsin I,PSD95,p-mTOR,and BDNF of the prefrontal cortex were significantly increased in the acupuncture group(P<0.05).At the 1 h and 24 h time points,compared with the normal group,the expression levels of synapsin I,PSD95,p-mTOR,and BDNF of the hippocampal tissues were significantly reduced in the model group(P<0.05).Compared with the model group,the expression levels of synapsin I,PSD95,p-mTOR,and BDNF of the hippocampus were not significantly different in the acupuncture group(P>0.05).Conclusion:Acupuncture may play a rapid antidepressant effect by increasing the expression of synaptic plasticity proteins in the prefrontal cortex.
基金supported by the National Natural Science Foundation of China,No.81373705the Natural Science Foundation of Hunan Province in China,No.13JJ3030
文摘Bushen Tiansui decoction is composed of six traditional Chinese medicines：Herba Epimedii,Radix Polygoni multiflori,Plastrum testudinis,Fossilia Ossis Mastodi,Radix Polygalae,and Rhizoma Acorus tatarinowii.Because Bushen Tiansui decoction is effective against amyloid beta（Aβ） toxicity,we hypothesized that it would reduce hippocampal synaptic damage and improve cognitive function in Alzheimer＇s disease.To test this hypothesis,we used a previously established animal model of Alzheimer＇s disease,that is,microinjection of aggregated Aβ25–35 into the bilateral brain ventricles of Sprague-Dawley rats.We found that long-term（28 days） oral administration of Bushen Tiansui decoction（0.563,1.688,and 3.375 g/m L;4 m L/day） prevented synaptic loss in the hippocampus and increased the expression levels of synaptic proteins,including postsynaptic density protein 95,the N-methyl-D-aspartate receptor 2 B subunit,and Shank1.These results suggested that Bushen Tiansui decoction can protect synapses by maintaining the expression of these synaptic proteins.Bushen Tiansui decoction also ameliorated measures reflecting spatial learning and memory deficits that were observed in the Morris water maze（i.e.,increased the number of platform crossings and the amount of time spent in the target quadrant and decreased escape latency） following intraventricular injections of aggregated Aβ25–35 compared with those measures in untreated Aβ_（25–35）-injected rats.Overall,these results provided evidence that further studies on the prevention and treatment of dementia with this traditional Chinese medicine are warranted.
基金supported by the National Natural Science Foundation of China,No.81772454(to TW)Natural Science Foundation of Jiangsu,China,No.BK20190655(to QL).
文摘Regular exercise has been shown to reduce the risk of Alzheimer’s disease(AD).Our previous study showed that the protein aquaporin 4(AQP4),which is specifically expressed on the paravascular processes of astrocytes,is necessary for glymphatic clearance of extracellular amyloid beta(Aβ)from the brain,which can delay the progression of Alzheimer’s disease.However,it is not known whether AQP4-regulated glymphatic clearance of extracellular Aβis involved in beneficial effects of exercise in AD patients.Our results showed that after 2 months of voluntary wheel exercise,APP/PS1 mice that were 3 months old at the start of the intervention exhibited a decrease in Aβburden,glial activation,perivascular AQP4 mislocalization,impaired glymphatic transport,synapse protein loss,and learning and memory defects compared with mice not subjected to the exercise intervention.In contrast,APP/PS1 mice that were 7 months old at the start of the intervention exhibited impaired AQP4 polarity and reduced glymphatic clearance of extracellular Aβ,and the above-mentioned impairments were not alleviated after the 2-month exercise intervention.Compared with age-matched APP/PS1 mice,AQP4 knockout APP/PS1 mice had more serious defects in glymphatic function,Aβplaque deposition,and cognitive impairment,which could not be alleviated after the exercise intervention.These findings suggest that AQP4-dependent glymphatic transport is the neurobiological basis for the beneficial effects of voluntary exercises that protect against the onset of AD.
文摘The slit diaphragm bridging the neighboring foot pro-cesses functions as a fnal barrier of glomerular capil-lary wall for preventing the leak of plasma proteins into primary urine. It is now accepted that the dysfunction of the sit diaphragm contributes to the development of proteinuria in several glomerular diseases. Neph-rin, a gene product of NPHS1, a gene for a congenital nephrotic syndrome of Finnish type, constitutes an ex-tracellular domain of the slit diaphragm. Podocin was identified as a gene product of NPHS2 , a gene for a familial steroid-resistant nephrotic syndrome of French. Podocin binds the cytoplasmic domain of nephrin. After then, CD2 associated protein, NEPH1 and transient re-ceptor potential-6 were also found as crucial molecules of the slit diaphragm. In order to explore other novel molecules contributing to the development of protein-uria, we performed a subtraction hybridization assay with a normal rat glomerular RNA and a glomerular RNA of rats with a puromycin aminonucleoside ne-phropathy, a mimic of a human minimal change type nephrotic syndrome. Then we have found that synaptic vesicle protein 2B, ephrin-B1 and neurexin were already downregulated at the early stage of puromycin aminonucleoside nephropathy, and that these molecules were localized close to nephrin. It is conceivable that these molecules are the slit diaphragm associated molecules, which participate in the regulation of the barrier func-tion. These molecules could be targets to establish a novel therapy for nephrotic syndrome.
基金Supported by National Natural Science Foundation of China:81673886Key R&D plan of the autonomous Region:2021BEB04023School level project of Ningxia Medical University:XT2020025。
文摘Stroke may cause upper motor neurons lesions, and thus limb spasm may occur. Brain plasticity refers to the brain's ability to change and adapt the environment and experience when the nervous system is damaged. Acupuncture can relieve the relevant pathological status due to stroke by enhancing brain plasticity. Specifically, acupuncture may finally achieve the balance between excitatory and inhibitory neurotransmitters by inhibiting the expression of neurotransmitter GABA, neurotrophic factor BDNF and proteins related to synaptic plasticity. This article analyzed and summarized that taking advantage of nervous plasticity the acupuncture could regenerate nervous cells and restore the related regulation of the movement by upper motor neurons, so as to relieving limb spasticity. It also summarized the research and application of acupuncture in regulating related signals, providing a systematic thought for the future study on acupuncture in the treatment of stroke induced limb.
基金supported by funding from the High-level New R&D Institute(2019B090904008)the High-level Innovative Research Institute(2021B0909050003)of the Department of Science and Technology of Guangdong Province+4 种基金National Science and Technology Innovation 2030 Major Program(2021ZD0200900)Shanghai Municipal Science and Technology Major Project(2018SHZDZX05)Zhongshan Municipal Bureau of Science and Technology(CXTD2022013)the National Science Fund for Distinguished Young Scholars(81825021)the funding from Zhongshan Municipal Bureau of Science and Technology(210724194041939).
文摘Epilepsy is a common neurological disorder that is primarily treated with antiseizure medications(ASMs).Although dozens of ASMs are available in the clinic,approximately 30%of epileptic patients have medically refractory seizures;other limitations in most traditional ASMs include poor tolerability and drug-drug interactions.Therefore,there is an urgent need to develop alternative ASMs.Levetiracetam(LEV)is a first-line ASM that is well tolerated,has promising efficacy,and has little drug-drug interaction.Although it is widely accepted that LEV acts through a unique therapeutic target synaptic vesicle protein(SV)2A,the molecular basis of its action remains unknown.Even so,the next-generation SV2A ligands against epilepsy based on the structure of LEV have achieved clinical success.This review highlights the research and development(R&D)process of LEV and its analogs,brivaracetam and padsevonil,to provide ideas and experience for the R&D of novel ASMs.
基金funding support from the National Natural Science Foundation of China(81971016)Shanghai Science and Technology program(21010502300)Construction project of Shanghai Key Laboratory of Molecular Imaging(18DZ2260400).
文摘Dementia is characterized by synaptic and neuronal dysfunction in disease-specific brain regions.Repeated failure of dementia clinical trials with therapeutic drugs targeting abnormal protein aggregates has caused researchers to shift their focus to synaptic functions and increased the importance of clinically available imaging for synaptic density and the development of synapse-targeted intervention.Synaptic density imaging with positron emission tomography(PET)tracer enables non-invasive detection of synaptic loss and hence investigates the association with other neuropathological events exemplified by disease-specific abnormal protein accumulation.Many studies have reviewed the progress of synaptic density imaging;however,to our knowledge,there is no article yet that summarizes the research progress of multimodal imaging of synaptic density tracers combined with other dementia biomarkers.Moreover,synaptic function intervention for dementia therapy has not yet been summarized.In this review,first we detail the progress of synaptic density imaging including tracer development and preclinical/clinical application,followed by a discussion of multimodal imaging of synaptic density tracers combined with classic dementia biomarkers in the clinical research stage.Finally,we briefly summarize the synapse-targeted drugs for dementia therapy.
基金supported by grants from Deutsche Forschungsgemeinschaft(DFG)(SFB1089,SCHO 820/4-1,SCHO 820/6-1,SCHO 820/7-1,SCHO 820/5-2,and SPP1757 to S.S.,SFB1089,SPP1757,INST117215,DI853/3-5&7,and INST 217/785-1 to D.D.),the BONFOR program of the University of Bonn Medical Center(S.S.and D.D.),and UCB Pharma.
文摘Synaptic vesicles can undergo several modes of exocytosis,endocytosis,and trafficking within individual synapses,and their fates may be linked to different vesicular protein compositions.Here,we mapped the intrasynaptic distribution of the synaptic vesicle proteins SV2B and SV2A in glutamatergic synapses of the hippocampus using three-dimensional electron microscopy.SV2B was almost completely absent from docked vesicles and a distinct cluster of vesicles found near the active zone.In contrast,SV2A was found in all domains of the synapse and was slightly enriched near the active zone.SV2B and SV2A were found on the membrane in the peri-active zone,suggesting the recycling from both clusters of vesicles.SV2B knockout mice displayed an increased seizure induction threshold only in a model employing high-frequency stimulation.Our data show that glutamatergic synapses generate molecularly distinct populations of synaptic vesicles and are able to maintain them at steep spatial gradients.The almost complete absence of SV2B from vesicles at the active zone of wildtype mice may explain why SV2A has been found more important for vesicle release.
