Alzheimer’s disease(AD)is the most common cause of dementia,characterized by progressive cognitive decline,and affects over 55 million people worldwide.AD is pathological featured by the aberrant accumulation of amyl...Alzheimer’s disease(AD)is the most common cause of dementia,characterized by progressive cognitive decline,and affects over 55 million people worldwide.AD is pathological featured by the aberrant accumulation of amyloid-βplaques,neurofibrillary tangles formed by hyperphosphorylated tau,synaptic loss,and dysfunction of neurotransmitter systems.Evidence from in vivo and autopsy studies has consistently shown that synaptic dysfunction and loss are strongly correlated with cognitive decline in AD,particularly in brain regions such as the hippocampus and cortex,which are critical for memory formation and processing.This perspective highlights recent histopathological findings related to synaptic dysfunction in AD,advancements in the development of imaging and fluid-based biomarkers for synaptic loss,and future studies.展开更多
With an increase in global aging,the number of people affected by cerebrovascular diseases is also increasing,and the incidence of vascular dementia-closely related to cerebrovascular risk-is increasing at an epidemic...With an increase in global aging,the number of people affected by cerebrovascular diseases is also increasing,and the incidence of vascular dementia-closely related to cerebrovascular risk-is increasing at an epidemic rate.However,few therapeutic options exist that can markedly improve the cognitive impairment and prognosis of vascular dementia patients.Similarly in Alzheimer’s disease and other neurological disorders,synaptic dysfunction is recognized as the main reason for cognitive decline.Nitric oxide is one of the ubiquitous gaseous cellular messengers involved in multiple physiological and pathological processes of the central nervous system.Recently,nitric oxide has been implicated in regulating synaptic plasticity and plays an important role in the pathogenesis of vascular dementia.This review introduces in detail the emerging role of nitric oxide in physiological and pathological states of vascular dementia and summarizes the diverse effects of nitric oxide on different aspects of synaptic dysfunction,neuroinflammation,oxidative stress,and blood-brain barrier dysfunction that underlie the progress of vascular dementia.Additionally,we propose that targeting the nitric oxide-sGC-cGMP pathway using certain specific approaches may provide a novel therapeutic strategy for vascular dementia.展开更多
Several experimental evidence suggests a link between brain Herpes simplex virus type-1 infection and the occurrence of Alzheimer’s disease.However,the molecular mechanisms underlying this association are not complet...Several experimental evidence suggests a link between brain Herpes simplex virus type-1 infection and the occurrence of Alzheimer’s disease.However,the molecular mechanisms underlying this association are not completely understood.Among the molecular mediators of synaptic and cognitive dysfunction occurring after Herpes simplex virus type-1 infection and reactivation in the brain neuroinflammatory cytokines seem to occupy a central role.Here,we specifically reviewed literature reports dealing with the impact of neuroinflammation on synaptic dysfunction observed after recurrent Herpes simplex virus type-1 reactivation in the brain,highlighting the role of interleukins and,in particular,interleukin 1βas a possible target against Herpes simplex virus type-1-induced neuronal dysfunctions.展开更多
The most prevalent form of dementia in the elderly is Alzheimer＇s disease.A significant contributing factor to the progression of the disease appears to be the progressive accumulation of amyloid-β42（Aβ42）,a smal...The most prevalent form of dementia in the elderly is Alzheimer＇s disease.A significant contributing factor to the progression of the disease appears to be the progressive accumulation of amyloid-β42（Aβ42）,a small hydrophobic peptide.Unfortunately,attempts to develop therapies targeting the accumulation of Aβ42 have not been successful to treat or even slow down the disease.It is possible that this failure is an indication that targeting downstream effects rather than the accumulation of the peptide itself might be a more effective approach.The accumulation of Aβ42 seems to affect various aspects of physiological cell functions.In this review,we provide an overview of the evidence that implicates Aβ42 in synaptic dysfunction,with a focus on how it contributes to defects in synaptic vesicle dynamics and neurotransmitter release.We discuss data that provide new insights on the Aβ42 induced pathology of Alzheimer＇s disease and a more detailed understanding of its contribution to the synaptic deficiencies that are associated with the early stages of the disease.Although the precise mechanisms that trigger synaptic dysfunction are still under investigation,the available data so far has enabled us to put forward a model that could be used as a guide to generate new therapeutic targets for pharmaceutical intervention.展开更多
Alzheimer's disease(AD) is an irreversible and progressive neurodegenerative disorder with no known cure or clear understanding of the mechanisms involved in the disease process.Amyloid plaques,neurofibrillary tan...Alzheimer's disease(AD) is an irreversible and progressive neurodegenerative disorder with no known cure or clear understanding of the mechanisms involved in the disease process.Amyloid plaques,neurofibrillary tangles and neuronal loss,though characteristic of AD,are late stage markers whose impact on the most devastating aspect of AD,namely memory loss and cognitive deficits,are still unclear.Recent studies demonstrate that structural and functional breakdown of synapses may be the underlying factor in AD-linked cognitive decline.One common element that presents with several features of AD is disrupted neuronal calcium signaling.Increased intracellular calcium levels are functionally linked to presenilin mutations,ApoE4 expression,amyloid plaques,tau tangles and synaptic dysfunction.In this review,we discuss the role of AD-linked calcium signaling alterations in neurons and how this may be linked to synaptic dysfunctions at both early and late stages of the disease.展开更多
Alzheimer's disease(AD)is a neurodegenerative disease characterized by progressive cognitive decline,accompanied by amyloid-β(Aβ)overload and hyperphosphorylated tau accumulation in the brain.Synaptic dysfunctio...Alzheimer's disease(AD)is a neurodegenerative disease characterized by progressive cognitive decline,accompanied by amyloid-β(Aβ)overload and hyperphosphorylated tau accumulation in the brain.Synaptic dysfunction,an important pathological hallmark in AD;is recognized as the main cause of the cognitive impairments.Accumulating evidence suggests that synaptic dysfunction could be an early pathological event in AD.Pathological tau,which is detached from axonal microtubules and mislocalized into pre-and postsynaptic neuronal compartments,is suggested to induce synaptic dysfunction in several ways,including reducing mobility and release of presynaptic vesicles,decreasing glutamatergic receptors,impairing the maturation of dendritic spines at postsynaptic terminals,disrupting mitochondrial transport and function in synapses,and promoting the phagocytosis of synapses by microglia.Here,we review the current understanding of how pathological tau mediates synaptic dysfunction and contributes to cognitive decline in AD.We propose that elucidating the mechanism by which pathological tau impairs synaptic function is essential for exploring novel therapeutic strategies for AD.展开更多
Astrocytes are integral components of the central nervous system,where they are involved in numerous functions critical for neuronal development and functioning,including maintenance of blood-brain barrier,formation o...Astrocytes are integral components of the central nervous system,where they are involved in numerous functions critical for neuronal development and functioning,including maintenance of blood-brain barrier,formation of synapses,supporting neurons with nutrients and trophic factors,and protecting them from injury.These roles are markedly affected in the course of chronic neurodegenerative disorders,often before the onset of the disease.In this review,we summarize the recent findings supporting the hypothesis that astrocytes play a fundamental role in the processes contributing to neurodegeneration.We focus onα-synucleinopathies and tauopathies as the most common neurodegenerative diseases.The mechanisms implicated in the development and progression of these disorders appear not to be exclusively neuronal,but are often related to the astrocytic-neuronal integrity and the response of astrocytes to the altered microglial function.A profound understanding of the multifaceted functions of astrocytes and identification of their communication pathways with neurons and microglia in health and in the disease is of critical significance for the development of novel mechanism-based therapies against neurodegenerative disorders.展开更多
Alzheimer＇s disease（AD） is the most common form of dementia in the older population, however, the precise cause of the disease is unknown. The neuropathology is characterized by the presence of aggregates formed by...Alzheimer＇s disease（AD） is the most common form of dementia in the older population, however, the precise cause of the disease is unknown. The neuropathology is characterized by the presence of aggregates formed by amyloid-β（Aβ） peptide and phosphorylated tau; which is accompanied by progressive impairment of memory. Diverse signaling pathways are linked to AD, and among these the Wnt signaling pathway is becoming increasingly relevant, since it plays essential roles in the adult brain. Initially, Wnt signaling activation was proposed as a neuroprotective mechanism against Aβ toxicity. Later, it was reported that it participates in tau phosphorylation and processes of learning and memory. Interestingly, in the last years we demonstrated that Wnt signaling is fundamental in amyloid precursor protein（APP） processing and that Wnt dysfunction results in Aβ production and aggregation in vitro. Recent in vivo studies reported that loss of canonical Wnt signaling exacerbates amyloid deposition in a transgenic（Tg） mouse model of AD. Finally, we showed that inhibition of Wnt signaling in a Tg mouse previously at the appearance of AD signs, resulted in memory loss, tau phosphorylation and Aβ formation and aggregation; indicating that Wnt dysfunction accelerated the onset of AD. More importantly, Wnt signaling loss promoted cognitive impairment, tau phosphorylation and Aβ1–42 production in the hippocampus of wild-type（WT） mice, contributing to the development of an Alzheimer＇s-like neurophatology. Therefore, in this review we highlight the importance of Wnt/β-catenin signaling dysfunction in the onset of AD and propose that the loss of canonical Wnt signaling is a triggering factor of AD.展开更多
Two of the most common neurodegenerative disorders-Alzheimer’s and Parkinson’s diseases-are characterized by synaptic dysfunction and degeneration that culminate in neuronal loss due to abnormal protein accumulation...Two of the most common neurodegenerative disorders-Alzheimer’s and Parkinson’s diseases-are characterized by synaptic dysfunction and degeneration that culminate in neuronal loss due to abnormal protein accumulation.The intracellular aggregation of hyper-phosphorylated tau and the extracellular aggregation of amyloid beta plaques form the basis of Alzheimer’s disease pathology.The major hallmark of Parkinson’s disease is the loss of dopaminergic neurons in the substantia nigra pars compacta,following the formation of Lewy bodies,which consists primarily of alpha-synuclein aggregates.However,the discrete mechanisms that contribute to neurodegeneration in these disorders are still poorly understood.Both neuronal loss and impaired adult neurogenesis have been reported in animal models of these disorders.Yet these findings remain subject to frequent debate due to a lack of conclusive evidence in post mortem brain tissue from human patients.While some publications provide significant findings related to axonal regeneration in Alzheimer’s and Parkinson’s diseases,they also highlight the limitations and obstacles to the development of neuroregenerative therapies.In this review,we summarize in vitro and in vivo findings related to neurogenesis,neuroregeneration and neurodegeneration in the context of Alzheimer’s and Parkinson’s diseases.展开更多
Beta amyloid （Aβ42）-induced dysfunction and loss of synapses are believed to be major underlying mechanisms for the progressive loss of learning and memory abilities in Alzheimer＇s disease （AD）. The vast majorit...Beta amyloid （Aβ42）-induced dysfunction and loss of synapses are believed to be major underlying mechanisms for the progressive loss of learning and memory abilities in Alzheimer＇s disease （AD）. The vast majority of investigations on AD-related synaptic impairment focus on synaptic plasticity, especially the decline of long-term potentiation of synaptic transmission caused by extracellular Aβ42. Changes in other aspects of synaptic and neuronal functions are less studied or undiscovered. Here, we report that intraneuronal accumulation of Aβ42 induced an age- dependent slowing of neuronal transmission along pathways involving multiple synapses.展开更多
Background Synaptic degeneration occurs in the early stage of Alzheimer’s disease(AD)before devastating symptoms,strongly correlated with cognitive decline.Circular RNAs(circRNAs)are abundantly enriched in neural tis...Background Synaptic degeneration occurs in the early stage of Alzheimer’s disease(AD)before devastating symptoms,strongly correlated with cognitive decline.Circular RNAs(circRNAs)are abundantly enriched in neural tissues,and aberrant expression of circRNAs precedes AD symptoms,significantly correlated with clinical dementia severity.However,the direct relationship between circRNA dysregulation and synaptic impairment in the early stage of AD remains poorly understood.Methods Hippocampal whole-transcriptome sequencing was performed to identify dysregulated circRNAs and miRNAs in 4-month-old wild-type and APP/PS1 mice.RNA antisense purification and mass spectrometry were utilized to unveil interactions between circRIMS2 and methyltransferase 3,N6-adenosine-methyltransferase complex catalytic subunit(METTL3).The roles of circRIMS2/miR-3968 in synaptic targeting of UBE2K-mediated ubiquitination of GluN2B subunit of NMDA receptor were evaluated via numerous lentiviruses followed by morphological staining,co-immunoprecipitation and behavioral testing.Further,a membrane-permeable peptide was used to block the ubiquitination of K1082 on GluN2B in AD mice.Results circRIMS2 was significantly upregulated in 4-month-old APP/PS1 mice,which was mediated by METTL3-dependent N6-methyladenosine(m6A)modification.Overexpression of circRIMS2 led to synaptic and memory impairments in 4-month-old C57BL/6 mice.MiR-3968/UBE2K was validated as the downstream of circRIMS2.Elevated UBE2K induced synaptic dysfunction of AD through ubiquitinating K1082 on GluN2B.Silencing METTL3 or blocking the ubiquitination of K1082 on GluN2B with a short membrane-permeable peptide remarkably rescued synaptic dysfunction in AD mice.Conclusions In conclusion,our study demonstrated that m6A-modified circRIMS2 mediates the synaptic and memory impairments in AD by activating the UBE2K-dependent ubiquitination and degradation of GluN2B via sponging miR-3968,providing novel therapeutic strategies for AD.展开更多
Synaptic dysfunction is a core component of the pathophysiology of schizophrenia.However,the genetic risk factors and molecular mechanisms related to synaptic dysfunction are still not fully understood.The Stonin 2(ST...Synaptic dysfunction is a core component of the pathophysiology of schizophrenia.However,the genetic risk factors and molecular mechanisms related to synaptic dysfunction are still not fully understood.The Stonin 2(STON2)gene encodes a major adaptor for clathrin-mediated endocytosis(CME)of synaptic vesicles.In this study,we showed that the C-C(307Pro-851Ala)haplotype of STON2 increases the susceptibility to schizophrenia and examined whether STON2 variations cause schizophrenia-like behaviors through the regulation of CME.We found that schizophrenia-related STON2 variations led to protein dephosphorylation,which affected its interaction with synaptotagmin 1(Syt1),a calcium sensor protein located in the presynaptic membrane that is critical for CME.STON2307Pro851Ala knockin mice exhibited deficits in synaptic transmission,short-term plasticity,and schizophrenia-like behaviors.Moreover,among seven antipsychotic drugs,patients with the C-C(307Pro-851Ala)haplotype responded better to haloperidol than did the T-A(307Ser-851Ser)carriers.The recovery of deficits in Syt1 sorting and synaptic transmission by acute administration of haloperidol effectively improved schizophrenia-like behaviors in STON2307Pro851Ala knockin mice.Our findings demonstrated the effect of schizophreniarelated STON2 variations on synaptic dysfunction through the regulation of CME,which might be attractive therapeutic targets for treating schizophrenia-like phenotypes.展开更多
基金supported by Swiss Center for Applied Human Toxicology(SCAHT AP22-01)(to RN).
文摘Alzheimer’s disease(AD)is the most common cause of dementia,characterized by progressive cognitive decline,and affects over 55 million people worldwide.AD is pathological featured by the aberrant accumulation of amyloid-βplaques,neurofibrillary tangles formed by hyperphosphorylated tau,synaptic loss,and dysfunction of neurotransmitter systems.Evidence from in vivo and autopsy studies has consistently shown that synaptic dysfunction and loss are strongly correlated with cognitive decline in AD,particularly in brain regions such as the hippocampus and cortex,which are critical for memory formation and processing.This perspective highlights recent histopathological findings related to synaptic dysfunction in AD,advancements in the development of imaging and fluid-based biomarkers for synaptic loss,and future studies.
基金supported by the National Key R&D Program of China,No.2019YFE0121200(to LQZ)the National Natural Science Foundation of China,Nos.82325017(to LQZ),82030032(to LQZ),82261138555(to DL)+2 种基金the Natural Science Foundation of Hubei Province,No.2022CFA004(to LQZ)the Natural Science Foundation of Jiangxi Province,No.20224BAB206040(to XZ)Research Project of Cognitive Science and Transdisciplinary Studies Center of Jiangxi Province,No.RZYB202201(to XZ).
文摘With an increase in global aging,the number of people affected by cerebrovascular diseases is also increasing,and the incidence of vascular dementia-closely related to cerebrovascular risk-is increasing at an epidemic rate.However,few therapeutic options exist that can markedly improve the cognitive impairment and prognosis of vascular dementia patients.Similarly in Alzheimer’s disease and other neurological disorders,synaptic dysfunction is recognized as the main reason for cognitive decline.Nitric oxide is one of the ubiquitous gaseous cellular messengers involved in multiple physiological and pathological processes of the central nervous system.Recently,nitric oxide has been implicated in regulating synaptic plasticity and plays an important role in the pathogenesis of vascular dementia.This review introduces in detail the emerging role of nitric oxide in physiological and pathological states of vascular dementia and summarizes the diverse effects of nitric oxide on different aspects of synaptic dysfunction,neuroinflammation,oxidative stress,and blood-brain barrier dysfunction that underlie the progress of vascular dementia.Additionally,we propose that targeting the nitric oxide-sGC-cGMP pathway using certain specific approaches may provide a novel therapeutic strategy for vascular dementia.
基金supported by UniversitàCattolica(D1 intramural funds to RP)Italian Ministry of University and Research(PRIN 2022ZYLB7B,P2022YW7BP funds to CG).
文摘Several experimental evidence suggests a link between brain Herpes simplex virus type-1 infection and the occurrence of Alzheimer’s disease.However,the molecular mechanisms underlying this association are not completely understood.Among the molecular mediators of synaptic and cognitive dysfunction occurring after Herpes simplex virus type-1 infection and reactivation in the brain neuroinflammatory cytokines seem to occupy a central role.Here,we specifically reviewed literature reports dealing with the impact of neuroinflammation on synaptic dysfunction observed after recurrent Herpes simplex virus type-1 reactivation in the brain,highlighting the role of interleukins and,in particular,interleukin 1βas a possible target against Herpes simplex virus type-1-induced neuronal dysfunctions.
文摘The most prevalent form of dementia in the elderly is Alzheimer＇s disease.A significant contributing factor to the progression of the disease appears to be the progressive accumulation of amyloid-β42（Aβ42）,a small hydrophobic peptide.Unfortunately,attempts to develop therapies targeting the accumulation of Aβ42 have not been successful to treat or even slow down the disease.It is possible that this failure is an indication that targeting downstream effects rather than the accumulation of the peptide itself might be a more effective approach.The accumulation of Aβ42 seems to affect various aspects of physiological cell functions.In this review,we provide an overview of the evidence that implicates Aβ42 in synaptic dysfunction,with a focus on how it contributes to defects in synaptic vesicle dynamics and neurotransmitter release.We discuss data that provide new insights on the Aβ42 induced pathology of Alzheimer＇s disease and a more detailed understanding of its contribution to the synaptic deficiencies that are associated with the early stages of the disease.Although the precise mechanisms that trigger synaptic dysfunction are still under investigation,the available data so far has enabled us to put forward a model that could be used as a guide to generate new therapeutic targets for pharmaceutical intervention.
文摘Alzheimer's disease(AD) is an irreversible and progressive neurodegenerative disorder with no known cure or clear understanding of the mechanisms involved in the disease process.Amyloid plaques,neurofibrillary tangles and neuronal loss,though characteristic of AD,are late stage markers whose impact on the most devastating aspect of AD,namely memory loss and cognitive deficits,are still unclear.Recent studies demonstrate that structural and functional breakdown of synapses may be the underlying factor in AD-linked cognitive decline.One common element that presents with several features of AD is disrupted neuronal calcium signaling.Increased intracellular calcium levels are functionally linked to presenilin mutations,ApoE4 expression,amyloid plaques,tau tangles and synaptic dysfunction.In this review,we discuss the role of AD-linked calcium signaling alterations in neurons and how this may be linked to synaptic dysfunctions at both early and late stages of the disease.
基金supported partially by the National Natural Science Foundation of China(82030032,32070960,81871108 to DL,81760221 and 81960221 to XPY,and 81660209 to ZYC)the National Science&Technology Fundamental Resource Investigation Program of China(2018FY100903 to XPY)Science and Technology Project Founded by the Education Department of Jiangxi Province(GJJ201834 to MXW).
文摘Alzheimer's disease(AD)is a neurodegenerative disease characterized by progressive cognitive decline,accompanied by amyloid-β(Aβ)overload and hyperphosphorylated tau accumulation in the brain.Synaptic dysfunction,an important pathological hallmark in AD;is recognized as the main cause of the cognitive impairments.Accumulating evidence suggests that synaptic dysfunction could be an early pathological event in AD.Pathological tau,which is detached from axonal microtubules and mislocalized into pre-and postsynaptic neuronal compartments,is suggested to induce synaptic dysfunction in several ways,including reducing mobility and release of presynaptic vesicles,decreasing glutamatergic receptors,impairing the maturation of dendritic spines at postsynaptic terminals,disrupting mitochondrial transport and function in synapses,and promoting the phagocytosis of synapses by microglia.Here,we review the current understanding of how pathological tau mediates synaptic dysfunction and contributes to cognitive decline in AD.We propose that elucidating the mechanism by which pathological tau impairs synaptic function is essential for exploring novel therapeutic strategies for AD.
基金statutory funds provided by the Polish Ministry of Science and Higher Education for Mossakowski Medical Research Centre Polish Academy of Sciences,Warsaw,Poland(9/2018,to LS)。
文摘Astrocytes are integral components of the central nervous system,where they are involved in numerous functions critical for neuronal development and functioning,including maintenance of blood-brain barrier,formation of synapses,supporting neurons with nutrients and trophic factors,and protecting them from injury.These roles are markedly affected in the course of chronic neurodegenerative disorders,often before the onset of the disease.In this review,we summarize the recent findings supporting the hypothesis that astrocytes play a fundamental role in the processes contributing to neurodegeneration.We focus onα-synucleinopathies and tauopathies as the most common neurodegenerative diseases.The mechanisms implicated in the development and progression of these disorders appear not to be exclusively neuronal,but are often related to the astrocytic-neuronal integrity and the response of astrocytes to the altered microglial function.A profound understanding of the multifaceted functions of astrocytes and identification of their communication pathways with neurons and microglia in health and in the disease is of critical significance for the development of novel mechanism-based therapies against neurodegenerative disorders.
基金supported by grants PFB (Basal Financing Program) 12/2007 from the Basal Centre for Excellence in Science and Technology and FONDECYT,No.1120156(to NCI)a pre-doctoral fellowship from the National Commission of Science and Technology of Chile(CONICYT)(to CTR)
文摘Alzheimer＇s disease（AD） is the most common form of dementia in the older population, however, the precise cause of the disease is unknown. The neuropathology is characterized by the presence of aggregates formed by amyloid-β（Aβ） peptide and phosphorylated tau; which is accompanied by progressive impairment of memory. Diverse signaling pathways are linked to AD, and among these the Wnt signaling pathway is becoming increasingly relevant, since it plays essential roles in the adult brain. Initially, Wnt signaling activation was proposed as a neuroprotective mechanism against Aβ toxicity. Later, it was reported that it participates in tau phosphorylation and processes of learning and memory. Interestingly, in the last years we demonstrated that Wnt signaling is fundamental in amyloid precursor protein（APP） processing and that Wnt dysfunction results in Aβ production and aggregation in vitro. Recent in vivo studies reported that loss of canonical Wnt signaling exacerbates amyloid deposition in a transgenic（Tg） mouse model of AD. Finally, we showed that inhibition of Wnt signaling in a Tg mouse previously at the appearance of AD signs, resulted in memory loss, tau phosphorylation and Aβ formation and aggregation; indicating that Wnt dysfunction accelerated the onset of AD. More importantly, Wnt signaling loss promoted cognitive impairment, tau phosphorylation and Aβ1–42 production in the hippocampus of wild-type（WT） mice, contributing to the development of an Alzheimer＇s-like neurophatology. Therefore, in this review we highlight the importance of Wnt/β-catenin signaling dysfunction in the onset of AD and propose that the loss of canonical Wnt signaling is a triggering factor of AD.
文摘Two of the most common neurodegenerative disorders-Alzheimer’s and Parkinson’s diseases-are characterized by synaptic dysfunction and degeneration that culminate in neuronal loss due to abnormal protein accumulation.The intracellular aggregation of hyper-phosphorylated tau and the extracellular aggregation of amyloid beta plaques form the basis of Alzheimer’s disease pathology.The major hallmark of Parkinson’s disease is the loss of dopaminergic neurons in the substantia nigra pars compacta,following the formation of Lewy bodies,which consists primarily of alpha-synuclein aggregates.However,the discrete mechanisms that contribute to neurodegeneration in these disorders are still poorly understood.Both neuronal loss and impaired adult neurogenesis have been reported in animal models of these disorders.Yet these findings remain subject to frequent debate due to a lack of conclusive evidence in post mortem brain tissue from human patients.While some publications provide significant findings related to axonal regeneration in Alzheimer’s and Parkinson’s diseases,they also highlight the limitations and obstacles to the development of neuroregenerative therapies.In this review,we summarize in vitro and in vivo findings related to neurogenesis,neuroregeneration and neurodegeneration in the context of Alzheimer’s and Parkinson’s diseases.
基金supported by the National Natural Science Foundation of China(81071026 and 81371400)the National Basic Research Development Program of China(2013CB530900)
文摘Beta amyloid （Aβ42）-induced dysfunction and loss of synapses are believed to be major underlying mechanisms for the progressive loss of learning and memory abilities in Alzheimer＇s disease （AD）. The vast majority of investigations on AD-related synaptic impairment focus on synaptic plasticity, especially the decline of long-term potentiation of synaptic transmission caused by extracellular Aβ42. Changes in other aspects of synaptic and neuronal functions are less studied or undiscovered. Here, we report that intraneuronal accumulation of Aβ42 induced an age- dependent slowing of neuronal transmission along pathways involving multiple synapses.
基金supported by the National Natural Science Foundation of China(82372337,81500925 to Xiong Wang,81801062 to Xiaoguang Li)Tongji Hospital(HUST)Foundation for Excellent Young Scientist(2020YQ01-11 to Xiong Wang)the Natural Science Foundation of Hubei Province(2022CFB150 to Huijun Li).
文摘Background Synaptic degeneration occurs in the early stage of Alzheimer’s disease(AD)before devastating symptoms,strongly correlated with cognitive decline.Circular RNAs(circRNAs)are abundantly enriched in neural tissues,and aberrant expression of circRNAs precedes AD symptoms,significantly correlated with clinical dementia severity.However,the direct relationship between circRNA dysregulation and synaptic impairment in the early stage of AD remains poorly understood.Methods Hippocampal whole-transcriptome sequencing was performed to identify dysregulated circRNAs and miRNAs in 4-month-old wild-type and APP/PS1 mice.RNA antisense purification and mass spectrometry were utilized to unveil interactions between circRIMS2 and methyltransferase 3,N6-adenosine-methyltransferase complex catalytic subunit(METTL3).The roles of circRIMS2/miR-3968 in synaptic targeting of UBE2K-mediated ubiquitination of GluN2B subunit of NMDA receptor were evaluated via numerous lentiviruses followed by morphological staining,co-immunoprecipitation and behavioral testing.Further,a membrane-permeable peptide was used to block the ubiquitination of K1082 on GluN2B in AD mice.Results circRIMS2 was significantly upregulated in 4-month-old APP/PS1 mice,which was mediated by METTL3-dependent N6-methyladenosine(m6A)modification.Overexpression of circRIMS2 led to synaptic and memory impairments in 4-month-old C57BL/6 mice.MiR-3968/UBE2K was validated as the downstream of circRIMS2.Elevated UBE2K induced synaptic dysfunction of AD through ubiquitinating K1082 on GluN2B.Silencing METTL3 or blocking the ubiquitination of K1082 on GluN2B with a short membrane-permeable peptide remarkably rescued synaptic dysfunction in AD mice.Conclusions In conclusion,our study demonstrated that m6A-modified circRIMS2 mediates the synaptic and memory impairments in AD by activating the UBE2K-dependent ubiquitination and degradation of GluN2B via sponging miR-3968,providing novel therapeutic strategies for AD.
基金supported by the Key Realm R&D Program of Guangdong Province(2019B030335001)the National Natural Science Foundation of China(82330042,81825009,82071541,81971283,82271576,and 82101570)+2 种基金Changping Laboratory(2021B-01-01)the China Postdoctoral Science Foundation(2021M690421)the Non-profit Central Research Institute Chinese Academy of Medical Sciences(2023-PT320-08).
文摘Synaptic dysfunction is a core component of the pathophysiology of schizophrenia.However,the genetic risk factors and molecular mechanisms related to synaptic dysfunction are still not fully understood.The Stonin 2(STON2)gene encodes a major adaptor for clathrin-mediated endocytosis(CME)of synaptic vesicles.In this study,we showed that the C-C(307Pro-851Ala)haplotype of STON2 increases the susceptibility to schizophrenia and examined whether STON2 variations cause schizophrenia-like behaviors through the regulation of CME.We found that schizophrenia-related STON2 variations led to protein dephosphorylation,which affected its interaction with synaptotagmin 1(Syt1),a calcium sensor protein located in the presynaptic membrane that is critical for CME.STON2307Pro851Ala knockin mice exhibited deficits in synaptic transmission,short-term plasticity,and schizophrenia-like behaviors.Moreover,among seven antipsychotic drugs,patients with the C-C(307Pro-851Ala)haplotype responded better to haloperidol than did the T-A(307Ser-851Ser)carriers.The recovery of deficits in Syt1 sorting and synaptic transmission by acute administration of haloperidol effectively improved schizophrenia-like behaviors in STON2307Pro851Ala knockin mice.Our findings demonstrated the effect of schizophreniarelated STON2 variations on synaptic dysfunction through the regulation of CME,which might be attractive therapeutic targets for treating schizophrenia-like phenotypes.
