Pseudounipolar neurons in the dorsal root ganglia(DRG),as the central nodes of primary sensory afferents,possess a distinctive T-junction that is not merely a morphological peculiarity but also performs complex roles ...Pseudounipolar neurons in the dorsal root ganglia(DRG),as the central nodes of primary sensory afferents,possess a distinctive T-junction that is not merely a morphological peculiarity but also performs complex roles in rapid,multiplexed shunting and regulation of sensory signals.This specialized geometry enables separation,filtering,and feedback regulation of neuronal signals,thereby coordinating peripheral and central responses at multiple levels.Recent advances,including spatial transcriptomics,single-cell sequencing,super-resolution microscopy,organoid models,and novel electrophysiological methods,have permitted more precise dissection of the T-junction's molecular composition,ion-channel distribution,and electrophysiological properties.Here,we review current knowledge of the T-junction's developmental regulation and multilayered molecular networks,and we detail its functional alterations in both physiological signaling and pathological pain states,with particular emphasis on ion-channel modulation,signal attenuation,and selective transmission mechanisms.Finally,we discuss contemporary pain-intervention approaches and prospects for precision-targeted therapies,aiming to provide a theoretical foundation for future studies in pain physiology and clinical translation.展开更多
Knee osteoarthritis(KOA)represents one of the most common causes of chronic pain.The high prevalence and disability rates of KOA impose a severe burden on both individuals and society.In contrast to cutaneous pain,KOA...Knee osteoarthritis(KOA)represents one of the most common causes of chronic pain.The high prevalence and disability rates of KOA impose a severe burden on both individuals and society.In contrast to cutaneous pain,KOA-induced joint pain is characterized as a deep tissue pain that potentially involves distinct subgroups of peripheral sensory neurons and central processing mechanisms.Furthermore,KOA pain is closely related to locomotion activity.Impaired sensorimotor integration and pain mutually reinforce each other in KOA,forming a vicious cycle that exacerbates disease progression.In this review,we highlight the key differences between KOA pain and cutaneous pain,and the latter has been extensively studied in the pain field.We hope to offer new insights into the central mechanisms and development of new treatment strategies for KOA based on the interactions between impaired sensorimotor integration and chronic joint pain.展开更多
The mechanistic target of rapamycin(m TOR) is a serine/threonine kinase that plays a pivotal role in cellular growth, proliferation, survival, and metabolism. In the central nervous system(CNS), the mTOR pathway regul...The mechanistic target of rapamycin(m TOR) is a serine/threonine kinase that plays a pivotal role in cellular growth, proliferation, survival, and metabolism. In the central nervous system(CNS), the mTOR pathway regulates diverse aspects of neural development and function. Genetic mutations within the m TOR pathway lead to severe neurodevelopmental disorders, collectively known as “mTORopathies”(Crino, 2020). Dysfunctions of m TOR, including both its hyperactivation and hypoactivation, have also been implicated in a wide spectrum of other neurodevelopmental and neurodegenerative conditions, highlighting its importance in CNS health.展开更多
Spinal cord injury results in permanent loss of neurological functions due to severance of neural networks.Transplantation of neural stem cells holds promise to repair disrupted connections.Yet,ensuring the survival a...Spinal cord injury results in permanent loss of neurological functions due to severance of neural networks.Transplantation of neural stem cells holds promise to repair disrupted connections.Yet,ensuring the survival and integration of neural stem cells into the host neural circuit remains a formidable challenge.Here,we investigated whether modifying the intrinsic properties of neural stem cells could enhance their integration post-transplantation.We focused on phosphatase and tensin homolog(PTEN),a well-characterized tumor suppressor known to critically regulate neuronal survival and axonal regeneration.By deleting Pten in mouse neural stem cells,we observed increased neurite outgrowth and enhanced resistance to neurotoxic environments in culture.Upon transplantation into injured spinal cords,Pten-deficient neural stem cells exhibited higher survival and more extensive rostrocaudal distribution.To examine the potential influence of partial PTEN suppression,rat neural stem cells were treated with short hairpin RNA targeting PTEN,and the PTEN knockdown resulted in significant improvements in neurite growth,survival,and neurosphere motility in vitro.Transplantation of sh PTEN-treated neural stem cells into the injured spinal cord also led to an increase in graft survival and migration to an extent similar to that of complete deletion.Moreover,PTEN suppression facilitated neurite elongation from NSC-derived neurons migrating from the lesion epicenter.These findings suggest that modifying intrinsic signaling pathways,such as PTEN,within neural stem cells could bolster their therapeutic efficacy,offering potential avenues for future regenerative strategies for spinal cord injury.展开更多
Downregulation of the inwardly rectifying potassium channel Kir4.1 is a key step for inducing retinal Müller cell activation and interaction with other glial cells,which is involved in retinal ganglion cell apopt...Downregulation of the inwardly rectifying potassium channel Kir4.1 is a key step for inducing retinal Müller cell activation and interaction with other glial cells,which is involved in retinal ganglion cell apoptosis in glaucoma.Modulation of Kir4.1 expression in Müller cells may therefore be a potential strategy for attenuating retinal ganglion cell damage in glaucoma.In this study,we identified seven predicted phosphorylation sites in Kir4.1 and constructed lentiviral expression systems expressing Kir4.1 mutated at each site to prevent phosphorylation.Following this,we treated Müller glial cells in vitro and in vivo with the m Glu R I agonist DHPG to induce Kir4.1 or Kir4.1 Tyr^(9)Asp overexpression.We found that both Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression inhibited activation of Müller glial cells.Subsequently,we established a rat model of chronic ocular hypertension by injecting microbeads into the anterior chamber and overexpressed Kir4.1 or Kir4.1 Tyr^(9)Asp in the eye,and observed similar results in Müller cells in vivo as those seen in vitro.Both Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression inhibited Müller cell activation,regulated the balance of Bax/Bcl-2,and reduced the m RNA and protein levels of pro-inflammatory factors,including interleukin-1βand tumor necrosis factor-α.Furthermore,we investigated the regulatory effects of Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression on the release of pro-inflammatory factors in a co-culture system of Müller glial cells and microglia.In this co-culture system,we observed elevated adenosine triphosphate concentrations in activated Müller cells,increased levels of translocator protein(a marker of microglial activation),and elevated interleukin-1βm RNA and protein levels in microglia induced by activated Müller cells.These changes could be reversed by Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression in Müller cells.Kir4.1 overexpression,but not Kir4.1 Tyr^(9)Asp overexpression,reduced the number of proliferative and migratory microglia induced by activated Müller cells.Collectively,these results suggest that the tyrosine residue at position nine in Kir4.1 may serve as a functional modulation site in the retina in an experimental model of glaucoma.Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression attenuated Müller cell activation,reduced ATP/P2X receptor–mediated interactions between glial cells,inhibited microglial activation,and decreased the synthesis and release of pro-inflammatory factors,consequently ameliorating retinal ganglion cell apoptosis in glaucoma.展开更多
The mature central nervous system(CNS,composed of the brain,spinal cord,olfactory and optic nerves)is unable to regenerate spontaneously after an insult,both in the cases of neurodegenerative diseases(for example Alzh...The mature central nervous system(CNS,composed of the brain,spinal cord,olfactory and optic nerves)is unable to regenerate spontaneously after an insult,both in the cases of neurodegenerative diseases(for example Alzheimer's or Parkinson's disease)or traumatic injuries(such as spinal cord lesions).In the last 20 years,the field has made significant progress in unlocking axon regrowth.展开更多
Traumatic spinal cord injury(SCI)is a pathological condition that impairs both sensorimotor and cognitive functions.While research has long focused on understanding the pathophysiology of SCI and developing treatments...Traumatic spinal cord injury(SCI)is a pathological condition that impairs both sensorimotor and cognitive functions.While research has long focused on understanding the pathophysiology of SCI and developing treatments,only a few studies have investigated the cellular and molecular consequences that occur in the brain after trauma.From the earliest stages,the injury triggers microglial activation,increased neuronal death,and reduced hippocampal neurogenesis in the dentate gyrus.展开更多
Vascular ageing is increasingly recognised as a key driver of cardiovascular and cerebrovascular disease rather than merely a passive consequence of chronological time.Progressive loss of endothelial regenerative capa...Vascular ageing is increasingly recognised as a key driver of cardiovascular and cerebrovascular disease rather than merely a passive consequence of chronological time.Progressive loss of endothelial regenerative capacity remains central to this process and is characterised by endothelial progenitor cell dysfunction,accumulation of senescent endothelial cells,and aberrant changes in the endothelial secretome.Taken together these alterations contribute to ineffective endothelial repair,chronic(low-grade)vascular inflammation and impaired endothelial barrier integrity and function,ultimately leading to vascular dysfunction.Over the past two decades,accumulating evidence from our group and others has provided mechanistic insight into how oxidative stress,redox imbalance,mitochondrial dysfunction and cellular senescence collectively impair endothelial(barrier)function and compromise overall vascular homeostasis.Age-dependent changes in progenitor cell number and function further limit the capacity of vasculature to respond to damage and stress.More recent work demonstrate that senolytics and senomorphics can preserve endothelial function and delay age-related vascular and cerebral barrier dysfunction in experimental models.This mini review supports an emerging framework that positions defective endothelial renewal as a critical driver of vascular ageing and endothelial dysfunction.We propose that concomitant application of senotherapeutics with progenitor cell-based or secretome-based approaches represents a critical next step in precision vascular medicine.展开更多
G protein-coupled receptor 37(GPR37)is an orphan receptor predominantly expressed in the brain,particularly in oligodendrocytes and certain types of neurons.Notably,it has been shown that the N-terminal domain of GPR3...G protein-coupled receptor 37(GPR37)is an orphan receptor predominantly expressed in the brain,particularly in oligodendrocytes and certain types of neurons.Notably,it has been shown that the N-terminal domain of GPR37 undergoes proteolysis under normal physiological conditions,resulting in the formation of cleaved receptor forms and the release of its ectodomain(ecto-GPR37)into the extracellular milieu(Mattila et al.,2021).Importantly,ecto-GPR37 density is increased in cerebrospinal fluid(CSF)of patients suffering from sporadic Parkinson’s disease(PD),together with an abnormal GPR37 processing in post-mortem PD substantia nigra(Moratóet al.,2021;Figure 1A).展开更多
This paper presents the cosmological neuroscientific view that Jesus was probably an extraordinary human being blessed with a Soul able to not just understand the divine nature of the world but also to communicate in ...This paper presents the cosmological neuroscientific view that Jesus was probably an extraordinary human being blessed with a Soul able to not just understand the divine nature of the world but also to communicate in some ways with its ultimate essence,which he identified in public as Moses’God but seemed to feel in his deepest moments that God is Spirit permeating the universe with love and truth.His teaching turned out to be a revolutionary new worldview identifying love,forgiveness,magnanimity,service for others,respect for truth,resistance to evil,trust in God and pursuing primarily spiritual treasures instead of material ones-as the expressions of human life’s true meaning.This necessarily led him to confrontations with his society’s leaders,who,both unreceptive to his challenging worldview and fearful for losing their power over the people’s minds,arrested him and arranged his death by crucifixion.Yet,by accepting this fate as unavoidable and going through his suffering with grace and understanding,he achieved the best’s admiration that soon transformed into worshipping him and finally into the creation of Christianity:a new religion moving forward human evolution,however with the cycles of glory and corruption so characteristic to our species.The paper implies Jesus’system of thoughts as a unique sound in the great symphony of civilization on Earth while it also harmonizes with the sounds of the Ten Commandments,the Sermon at Benares,the Tao Te Ching,the Koran,as well as those of the philosophies of Alexander von Humboldt,Alfred Russel Wallace,Rabindranath Tagore,Kahlil Gibran,Albert Schweitzer,and their likes.展开更多
Over a century ago,the first clinical and neuropathological insights into major neurodegenerative diseases began to emerge:the description of Alzheimer’s disease(AD)by Alois Alzheimer in 1906,frontotemporal dementia ...Over a century ago,the first clinical and neuropathological insights into major neurodegenerative diseases began to emerge:the description of Alzheimer’s disease(AD)by Alois Alzheimer in 1906,frontotemporal dementia by Arnold Pick in the same years,and Lewy bodies by Friedrich Lewy in 1912.These foundational studies laid the groundwork for the classification of what we now recognize as distinct neurodegenerative entities(Allali,2024).展开更多
Neural stem cells(NSCs)and glioblastoma stem cells(GSCs)share a complex regulatory landscape in which cholinergic signaling plays a pivotal role in both neural development and tumor progression.While acetylcholine(ACh...Neural stem cells(NSCs)and glioblastoma stem cells(GSCs)share a complex regulatory landscape in which cholinergic signaling plays a pivotal role in both neural development and tumor progression.While acetylcholine(ACh)regulates NSC quiescence and differentiation within neurogenic niches,glioblastoma cells exploit th ese pathways to enhance their adaptability and invasiveness.The involvement of muscarinic(M3)and nicotinic(α7)receptors in both cell types suggests that glioblastoma retains neural progenitor-like traits,contributing to its plasticity and resilience.This article explores the shared cholinergic mechanisms between NSCs and GSCs,highlighting their role in both neural development and glioblastoma progression.展开更多
Alzheimer’s disease(AD)and other tauopathies are characterized by the accumulation of misfolded tau protein,which forms toxic oligomers that contribute to synaptic dysfunction and neuronal loss.Here,we briefly discus...Alzheimer’s disease(AD)and other tauopathies are characterized by the accumulation of misfolded tau protein,which forms toxic oligomers that contribute to synaptic dysfunction and neuronal loss.Here,we briefly discuss recent findings indicating that the cellular prion protein(PrPC)plays a critical role in mediating the synaptotoxic effects of tau oligomers(TauOs),offering new insights into disease pathogenesis and potential therapeutic strategies.展开更多
Oxidative stress has long been implicated as a driving force in neurodegenerative disease,with studies of human brain tissue and animal models revealing its important role.Parkinson’s disease(PD),in particular,highli...Oxidative stress has long been implicated as a driving force in neurodegenerative disease,with studies of human brain tissue and animal models revealing its important role.Parkinson’s disease(PD),in particular,highlights the selective vulnerability of neurons to the insults of reactive oxygen species.The motor symptoms of PD are caused by degeneration of dopamine neurons in the substantia nigra.These neurons experience increased oxidative stress due in part to highly active mitochondria that support their high bioenergetic demand and the generation of reactive oxygen species by dopamine metabolism(Watanabe et al.,2024).展开更多
The innate immune system of the central nervous system(CNS),long viewed as primarily microgliadriven,is now increasingly recognized to include astrocytes as active participants in neuroimmune signaling.Chronic alcohol...The innate immune system of the central nervous system(CNS),long viewed as primarily microgliadriven,is now increasingly recognized to include astrocytes as active participants in neuroimmune signaling.Chronic alcohol exposure trigge rs oxidative stress,glial activation,and sustained inflammation,ultimately contributing to cognitive decline and neuronal injury.展开更多
Alzheimer's disease and Down syndrome:Down syndrome(DS)is a genetic disorder caused by the presence of an extra complete or partial chromosome 21.Over the past few decades,significant advancements in medical treat...Alzheimer's disease and Down syndrome:Down syndrome(DS)is a genetic disorder caused by the presence of an extra complete or partial chromosome 21.Over the past few decades,significant advancements in medical treatment and nursing care have greatly improved the life expectancy of individuals with DS.However,as they age,their risk of developing Alzheimer’s disease(AD)increases considerably(Antonarakis et al.,2020).展开更多
Noninvasive brain stimulation techniques offer promising therapeutic and regenerative prospects in neurological diseases by modulating brain activity and improving cognitive and motor functions.Given the paucity of kn...Noninvasive brain stimulation techniques offer promising therapeutic and regenerative prospects in neurological diseases by modulating brain activity and improving cognitive and motor functions.Given the paucity of knowledge about the underlying modes of action and optimal treatment modalities,a thorough translational investigation of noninvasive brain stimulation in preclinical animal models is urgently needed.Thus,we reviewed the current literature on the mechanistic underpinnings of noninvasive brain stimulation in models of central nervous system impairment,with a particular emphasis on traumatic brain injury and stroke.Due to the lack of translational models in most noninvasive brain stimulation techniques proposed,we found this review to the most relevant techniques used in humans,i.e.,transcranial magnetic stimulation and transcranial direct current stimulation.We searched the literature in Pub Med,encompassing the MEDLINE and PMC databases,for studies published between January 1,2020 and September 30,2024.Thirty-five studies were eligible.Transcranial magnetic stimulation and transcranial direct current stimulation demonstrated distinct strengths in augmenting rehabilitation post-stroke and traumatic brain injury,with emerging mechanistic evidence.Overall,we identified neuronal,inflammatory,microvascular,and apoptotic pathways highlighted in the literature.This review also highlights a lack of translational surrogate parameters to bridge the gap between preclinical findings and their clinical translation.展开更多
Astrocytes have important neurosupportive functions in the brain that are altered in neurodegenerative diseases by unresolved mechanisms.We showed previously that astrocytes cultured from mice transgenic for human P30...Astrocytes have important neurosupportive functions in the brain that are altered in neurodegenerative diseases by unresolved mechanisms.We showed previously that astrocytes cultured from mice transgenic for human P301S-tau(P301S-mice)recapitulate the deficit in production and secretion of thrombospondin1 found in symptomatic P301S mouse brains,causing both reduced synapse formation and survival of cultured neurons.To further characterize how P301S-derived astrocytes differ from controls,we have compared the astrocyte-conditioned media of cultured astrocytes from postnatal day 7/8 P301S mice(P301S-astrocyte-conditioned media)versus controls(C57-astrocyte-conditioned media)using label-free liquid chromatography-mass spectrometry.We verified that thrombospondin1 secretion was significantly reduced in the P301S-astrocyte-conditioned media versus C57-astrocyte-conditioned media,demonstrating the robustness of the analysis.The most notable distinction was that~57%of the P301S-astrocyte-conditioned media-enriched proteins were cytoplasmic proteins linked to cellular metabolism that are not predicted to be secreted via classical or non-classical secretion pathways,whereas~88%of C57-astrocyte-conditioned media-enriched proteins comprised classically secreted proteins enriched in extracellular matrix components.These differences are associated with the finding that P301S-derived cultured astrocytes were smaller and in vivo appeared less mature in the cortex of P301S mice.The unconventional secretion pathway that P301S-astrocyte-conditioned media display shares similarities with several amyloid-β-exposed astrocyte-conditioned media,indicating that stimuli induced by tau and amyloid-βmay induce a common adverse response pathway.Altogether,members of this adverse pathway may serve as a potential set of biomarkers to aid the clinical diagnosis of Alzheimer’s disease and other tauopathies,while the list of reduced neurosupportive factors could indicate new approaches to enhance neuronal survival by factor supplementation in tauopathies.展开更多
Multiple sclerosis(MS)is a chronic disorder of the central nervous system characterized by multifocal lesions where inflammation,demyelination,and neurodegeneration occur(Jakimovski et al.,2024).MS diagnosis primarily...Multiple sclerosis(MS)is a chronic disorder of the central nervous system characterized by multifocal lesions where inflammation,demyelination,and neurodegeneration occur(Jakimovski et al.,2024).MS diagnosis primarily relies on the demonstration of dissemination in time and space of the lesions based on clinical,magnetic resonance imaging(MRI),and cerebrospinal fluid assessments(Jakimovski et al.,2024).展开更多
Microglia are the resident macrophages of the central nervous system.They act as the first line of defense against pathogens and play essential roles in neuroinflammation and tissue repair after brain insult or in neu...Microglia are the resident macrophages of the central nervous system.They act as the first line of defense against pathogens and play essential roles in neuroinflammation and tissue repair after brain insult or in neurodegenerative and demyelinating diseases(Borst et al.,2021).Together with infiltrating monocyte-derived macrophages,microglia also play a critical role for brain tumor development,since immunosuppressive interactions between tumor cells and tumor-associated microglia and macrophages(TAM)are linked to malignant progression.This mechanism is of particular relevance in glioblastoma(GB),the deadliest form of brain cancer with a median overall survival of less than 15 months(Khan et al.,2023).Therefore,targeting microglia and macrophage activation is a promising strategy for therapeutic interference in brain disease.展开更多
基金supported by grant from the National Key Technology Support Program of the Ministry of Science and Technology of China(No.2021ZD0203204)。
文摘Pseudounipolar neurons in the dorsal root ganglia(DRG),as the central nodes of primary sensory afferents,possess a distinctive T-junction that is not merely a morphological peculiarity but also performs complex roles in rapid,multiplexed shunting and regulation of sensory signals.This specialized geometry enables separation,filtering,and feedback regulation of neuronal signals,thereby coordinating peripheral and central responses at multiple levels.Recent advances,including spatial transcriptomics,single-cell sequencing,super-resolution microscopy,organoid models,and novel electrophysiological methods,have permitted more precise dissection of the T-junction's molecular composition,ion-channel distribution,and electrophysiological properties.Here,we review current knowledge of the T-junction's developmental regulation and multilayered molecular networks,and we detail its functional alterations in both physiological signaling and pathological pain states,with particular emphasis on ion-channel modulation,signal attenuation,and selective transmission mechanisms.Finally,we discuss contemporary pain-intervention approaches and prospects for precision-targeted therapies,aiming to provide a theoretical foundation for future studies in pain physiology and clinical translation.
基金supported by the Natural Science Foundation of Beijing Municipality(No.F252065)the National Natural Science Foundation of China(No.32271190,32571323)the STI 2030 Major Project(No.2021ZD0203202)。
文摘Knee osteoarthritis(KOA)represents one of the most common causes of chronic pain.The high prevalence and disability rates of KOA impose a severe burden on both individuals and society.In contrast to cutaneous pain,KOA-induced joint pain is characterized as a deep tissue pain that potentially involves distinct subgroups of peripheral sensory neurons and central processing mechanisms.Furthermore,KOA pain is closely related to locomotion activity.Impaired sensorimotor integration and pain mutually reinforce each other in KOA,forming a vicious cycle that exacerbates disease progression.In this review,we highlight the key differences between KOA pain and cutaneous pain,and the latter has been extensively studied in the pain field.We hope to offer new insights into the central mechanisms and development of new treatment strategies for KOA based on the interactions between impaired sensorimotor integration and chronic joint pain.
基金supported by grants from Simons Foundation (SFARI 479754),CIHR (PJT-180565)the Scottish Rite Charitable Foundation of Canada (to YL)funding from the Canada Research Chairs program。
文摘The mechanistic target of rapamycin(m TOR) is a serine/threonine kinase that plays a pivotal role in cellular growth, proliferation, survival, and metabolism. In the central nervous system(CNS), the mTOR pathway regulates diverse aspects of neural development and function. Genetic mutations within the m TOR pathway lead to severe neurodevelopmental disorders, collectively known as “mTORopathies”(Crino, 2020). Dysfunctions of m TOR, including both its hyperactivation and hypoactivation, have also been implicated in a wide spectrum of other neurodevelopmental and neurodegenerative conditions, highlighting its importance in CNS health.
基金supported by the National Research Foundation of Korea,Nos.2021R1A2C2006110,2021M3E5D9021364,2019R1A5A2026045(to BGK)the Korea Initiative for Fostering University of Research and Innovation(KIURI)Program of the NRF funded by the MSIT(to HK),No.NRF2021M3H1A104892211(to HSK)。
文摘Spinal cord injury results in permanent loss of neurological functions due to severance of neural networks.Transplantation of neural stem cells holds promise to repair disrupted connections.Yet,ensuring the survival and integration of neural stem cells into the host neural circuit remains a formidable challenge.Here,we investigated whether modifying the intrinsic properties of neural stem cells could enhance their integration post-transplantation.We focused on phosphatase and tensin homolog(PTEN),a well-characterized tumor suppressor known to critically regulate neuronal survival and axonal regeneration.By deleting Pten in mouse neural stem cells,we observed increased neurite outgrowth and enhanced resistance to neurotoxic environments in culture.Upon transplantation into injured spinal cords,Pten-deficient neural stem cells exhibited higher survival and more extensive rostrocaudal distribution.To examine the potential influence of partial PTEN suppression,rat neural stem cells were treated with short hairpin RNA targeting PTEN,and the PTEN knockdown resulted in significant improvements in neurite growth,survival,and neurosphere motility in vitro.Transplantation of sh PTEN-treated neural stem cells into the injured spinal cord also led to an increase in graft survival and migration to an extent similar to that of complete deletion.Moreover,PTEN suppression facilitated neurite elongation from NSC-derived neurons migrating from the lesion epicenter.These findings suggest that modifying intrinsic signaling pathways,such as PTEN,within neural stem cells could bolster their therapeutic efficacy,offering potential avenues for future regenerative strategies for spinal cord injury.
基金supported by the National Natural Science Foundation of China,Nos.32271043(to ZW)and 82171047(to YM)the both Science and Technology Major Project of Shanghai,No.2018SHZDZX01 and ZJLabShanghai Center for Brain Science and Brain-Inspired Technology(to ZW)。
文摘Downregulation of the inwardly rectifying potassium channel Kir4.1 is a key step for inducing retinal Müller cell activation and interaction with other glial cells,which is involved in retinal ganglion cell apoptosis in glaucoma.Modulation of Kir4.1 expression in Müller cells may therefore be a potential strategy for attenuating retinal ganglion cell damage in glaucoma.In this study,we identified seven predicted phosphorylation sites in Kir4.1 and constructed lentiviral expression systems expressing Kir4.1 mutated at each site to prevent phosphorylation.Following this,we treated Müller glial cells in vitro and in vivo with the m Glu R I agonist DHPG to induce Kir4.1 or Kir4.1 Tyr^(9)Asp overexpression.We found that both Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression inhibited activation of Müller glial cells.Subsequently,we established a rat model of chronic ocular hypertension by injecting microbeads into the anterior chamber and overexpressed Kir4.1 or Kir4.1 Tyr^(9)Asp in the eye,and observed similar results in Müller cells in vivo as those seen in vitro.Both Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression inhibited Müller cell activation,regulated the balance of Bax/Bcl-2,and reduced the m RNA and protein levels of pro-inflammatory factors,including interleukin-1βand tumor necrosis factor-α.Furthermore,we investigated the regulatory effects of Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression on the release of pro-inflammatory factors in a co-culture system of Müller glial cells and microglia.In this co-culture system,we observed elevated adenosine triphosphate concentrations in activated Müller cells,increased levels of translocator protein(a marker of microglial activation),and elevated interleukin-1βm RNA and protein levels in microglia induced by activated Müller cells.These changes could be reversed by Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression in Müller cells.Kir4.1 overexpression,but not Kir4.1 Tyr^(9)Asp overexpression,reduced the number of proliferative and migratory microglia induced by activated Müller cells.Collectively,these results suggest that the tyrosine residue at position nine in Kir4.1 may serve as a functional modulation site in the retina in an experimental model of glaucoma.Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression attenuated Müller cell activation,reduced ATP/P2X receptor–mediated interactions between glial cells,inhibited microglial activation,and decreased the synthesis and release of pro-inflammatory factors,consequently ameliorating retinal ganglion cell apoptosis in glaucoma.
基金supported by ANR(ANR-21CE16-0008-01)ANR(ANR-21-CE16-0008-02 and ANR-23CE52-0007)+1 种基金UNADEV(A22018CS)(to HN)UNADEV(A22020CS)(to SB)。
文摘The mature central nervous system(CNS,composed of the brain,spinal cord,olfactory and optic nerves)is unable to regenerate spontaneously after an insult,both in the cases of neurodegenerative diseases(for example Alzheimer's or Parkinson's disease)or traumatic injuries(such as spinal cord lesions).In the last 20 years,the field has made significant progress in unlocking axon regrowth.
文摘Traumatic spinal cord injury(SCI)is a pathological condition that impairs both sensorimotor and cognitive functions.While research has long focused on understanding the pathophysiology of SCI and developing treatments,only a few studies have investigated the cellular and molecular consequences that occur in the brain after trauma.From the earliest stages,the injury triggers microglial activation,increased neuronal death,and reduced hippocampal neurogenesis in the dentate gyrus.
文摘Vascular ageing is increasingly recognised as a key driver of cardiovascular and cerebrovascular disease rather than merely a passive consequence of chronological time.Progressive loss of endothelial regenerative capacity remains central to this process and is characterised by endothelial progenitor cell dysfunction,accumulation of senescent endothelial cells,and aberrant changes in the endothelial secretome.Taken together these alterations contribute to ineffective endothelial repair,chronic(low-grade)vascular inflammation and impaired endothelial barrier integrity and function,ultimately leading to vascular dysfunction.Over the past two decades,accumulating evidence from our group and others has provided mechanistic insight into how oxidative stress,redox imbalance,mitochondrial dysfunction and cellular senescence collectively impair endothelial(barrier)function and compromise overall vascular homeostasis.Age-dependent changes in progenitor cell number and function further limit the capacity of vasculature to respond to damage and stress.More recent work demonstrate that senolytics and senomorphics can preserve endothelial function and delay age-related vascular and cerebral barrier dysfunction in experimental models.This mini review supports an emerging framework that positions defective endothelial renewal as a critical driver of vascular ageing and endothelial dysfunction.We propose that concomitant application of senotherapeutics with progenitor cell-based or secretome-based approaches represents a critical next step in precision vascular medicine.
基金FEDER/Ministerio de Ciencia,Innovacióny Universidades-Agencia Estatal de Investigación(PID2023-147425OB-I00 to FC)Agència de Gestiód’Ajuts Universitaris i de Recerca(AGAUR)-Generalitat de Catalunya(2021 SGR 00698 to FC).
文摘G protein-coupled receptor 37(GPR37)is an orphan receptor predominantly expressed in the brain,particularly in oligodendrocytes and certain types of neurons.Notably,it has been shown that the N-terminal domain of GPR37 undergoes proteolysis under normal physiological conditions,resulting in the formation of cleaved receptor forms and the release of its ectodomain(ecto-GPR37)into the extracellular milieu(Mattila et al.,2021).Importantly,ecto-GPR37 density is increased in cerebrospinal fluid(CSF)of patients suffering from sporadic Parkinson’s disease(PD),together with an abnormal GPR37 processing in post-mortem PD substantia nigra(Moratóet al.,2021;Figure 1A).
文摘This paper presents the cosmological neuroscientific view that Jesus was probably an extraordinary human being blessed with a Soul able to not just understand the divine nature of the world but also to communicate in some ways with its ultimate essence,which he identified in public as Moses’God but seemed to feel in his deepest moments that God is Spirit permeating the universe with love and truth.His teaching turned out to be a revolutionary new worldview identifying love,forgiveness,magnanimity,service for others,respect for truth,resistance to evil,trust in God and pursuing primarily spiritual treasures instead of material ones-as the expressions of human life’s true meaning.This necessarily led him to confrontations with his society’s leaders,who,both unreceptive to his challenging worldview and fearful for losing their power over the people’s minds,arrested him and arranged his death by crucifixion.Yet,by accepting this fate as unavoidable and going through his suffering with grace and understanding,he achieved the best’s admiration that soon transformed into worshipping him and finally into the creation of Christianity:a new religion moving forward human evolution,however with the cycles of glory and corruption so characteristic to our species.The paper implies Jesus’system of thoughts as a unique sound in the great symphony of civilization on Earth while it also harmonizes with the sounds of the Ten Commandments,the Sermon at Benares,the Tao Te Ching,the Koran,as well as those of the philosophies of Alexander von Humboldt,Alfred Russel Wallace,Rabindranath Tagore,Kahlil Gibran,Albert Schweitzer,and their likes.
文摘Over a century ago,the first clinical and neuropathological insights into major neurodegenerative diseases began to emerge:the description of Alzheimer’s disease(AD)by Alois Alzheimer in 1906,frontotemporal dementia by Arnold Pick in the same years,and Lewy bodies by Friedrich Lewy in 1912.These foundational studies laid the groundwork for the classification of what we now recognize as distinct neurodegenerative entities(Allali,2024).
文摘Neural stem cells(NSCs)and glioblastoma stem cells(GSCs)share a complex regulatory landscape in which cholinergic signaling plays a pivotal role in both neural development and tumor progression.While acetylcholine(ACh)regulates NSC quiescence and differentiation within neurogenic niches,glioblastoma cells exploit th ese pathways to enhance their adaptability and invasiveness.The involvement of muscarinic(M3)and nicotinic(α7)receptors in both cell types suggests that glioblastoma retains neural progenitor-like traits,contributing to its plasticity and resilience.This article explores the shared cholinergic mechanisms between NSCs and GSCs,highlighting their role in both neural development and glioblastoma progression.
基金supported by the Italian Ministry of Health grant RF-2021-12372337(to GF and CB).
文摘Alzheimer’s disease(AD)and other tauopathies are characterized by the accumulation of misfolded tau protein,which forms toxic oligomers that contribute to synaptic dysfunction and neuronal loss.Here,we briefly discuss recent findings indicating that the cellular prion protein(PrPC)plays a critical role in mediating the synaptotoxic effects of tau oligomers(TauOs),offering new insights into disease pathogenesis and potential therapeutic strategies.
基金supported by OHSU Neurology Foundation Funds and NIH Grant R01NS119226 to IM.
文摘Oxidative stress has long been implicated as a driving force in neurodegenerative disease,with studies of human brain tissue and animal models revealing its important role.Parkinson’s disease(PD),in particular,highlights the selective vulnerability of neurons to the insults of reactive oxygen species.The motor symptoms of PD are caused by degeneration of dopamine neurons in the substantia nigra.These neurons experience increased oxidative stress due in part to highly active mitochondria that support their high bioenergetic demand and the generation of reactive oxygen species by dopamine metabolism(Watanabe et al.,2024).
基金supported by startup funding from UNMC to Dr.PPpartially by the National Institute on Alcohol Abuse and Alcoholism (AA031444 and P50AA030407-5126,Pilot Core grant) to Dr.SS
文摘The innate immune system of the central nervous system(CNS),long viewed as primarily microgliadriven,is now increasingly recognized to include astrocytes as active participants in neuroimmune signaling.Chronic alcohol exposure trigge rs oxidative stress,glial activation,and sustained inflammation,ultimately contributing to cognitive decline and neuronal injury.
文摘Alzheimer's disease and Down syndrome:Down syndrome(DS)is a genetic disorder caused by the presence of an extra complete or partial chromosome 21.Over the past few decades,significant advancements in medical treatment and nursing care have greatly improved the life expectancy of individuals with DS.However,as they age,their risk of developing Alzheimer’s disease(AD)increases considerably(Antonarakis et al.,2020).
基金funded by the Deutsche Forschungsgemeinschaft(DFG,German Research Foundation):project ID 431549029-SFB 1451the Marga-und-Walter-Boll-Stiftung(#210-10-15)(to MAR)a stipend from the'Gerok Program'(Faculty of Medicine,University of Cologne,Germany)。
文摘Noninvasive brain stimulation techniques offer promising therapeutic and regenerative prospects in neurological diseases by modulating brain activity and improving cognitive and motor functions.Given the paucity of knowledge about the underlying modes of action and optimal treatment modalities,a thorough translational investigation of noninvasive brain stimulation in preclinical animal models is urgently needed.Thus,we reviewed the current literature on the mechanistic underpinnings of noninvasive brain stimulation in models of central nervous system impairment,with a particular emphasis on traumatic brain injury and stroke.Due to the lack of translational models in most noninvasive brain stimulation techniques proposed,we found this review to the most relevant techniques used in humans,i.e.,transcranial magnetic stimulation and transcranial direct current stimulation.We searched the literature in Pub Med,encompassing the MEDLINE and PMC databases,for studies published between January 1,2020 and September 30,2024.Thirty-five studies were eligible.Transcranial magnetic stimulation and transcranial direct current stimulation demonstrated distinct strengths in augmenting rehabilitation post-stroke and traumatic brain injury,with emerging mechanistic evidence.Overall,we identified neuronal,inflammatory,microvascular,and apoptotic pathways highlighted in the literature.This review also highlights a lack of translational surrogate parameters to bridge the gap between preclinical findings and their clinical translation.
基金MGS from the Alzheimer Society(#384,AS-PG-17-026),Alzheimer’s Research UK(ART-PG2011-20 and ARUK-EXT2015B-2)the BBSRC(BB/T509085/1)+1 种基金The Fondation Recherche Alzheimer(G112606)the Scholl Foundation,and to MGS and AMT from the National Center for the Replacement,Refinement,&Reduction of Animals in Research(NC3R)(#NC/L000741/1).
文摘Astrocytes have important neurosupportive functions in the brain that are altered in neurodegenerative diseases by unresolved mechanisms.We showed previously that astrocytes cultured from mice transgenic for human P301S-tau(P301S-mice)recapitulate the deficit in production and secretion of thrombospondin1 found in symptomatic P301S mouse brains,causing both reduced synapse formation and survival of cultured neurons.To further characterize how P301S-derived astrocytes differ from controls,we have compared the astrocyte-conditioned media of cultured astrocytes from postnatal day 7/8 P301S mice(P301S-astrocyte-conditioned media)versus controls(C57-astrocyte-conditioned media)using label-free liquid chromatography-mass spectrometry.We verified that thrombospondin1 secretion was significantly reduced in the P301S-astrocyte-conditioned media versus C57-astrocyte-conditioned media,demonstrating the robustness of the analysis.The most notable distinction was that~57%of the P301S-astrocyte-conditioned media-enriched proteins were cytoplasmic proteins linked to cellular metabolism that are not predicted to be secreted via classical or non-classical secretion pathways,whereas~88%of C57-astrocyte-conditioned media-enriched proteins comprised classically secreted proteins enriched in extracellular matrix components.These differences are associated with the finding that P301S-derived cultured astrocytes were smaller and in vivo appeared less mature in the cortex of P301S mice.The unconventional secretion pathway that P301S-astrocyte-conditioned media display shares similarities with several amyloid-β-exposed astrocyte-conditioned media,indicating that stimuli induced by tau and amyloid-βmay induce a common adverse response pathway.Altogether,members of this adverse pathway may serve as a potential set of biomarkers to aid the clinical diagnosis of Alzheimer’s disease and other tauopathies,while the list of reduced neurosupportive factors could indicate new approaches to enhance neuronal survival by factor supplementation in tauopathies.
基金supported by Italian Ministry for Health(RF-2011-02349698,RF-2018-12367731)(to CF).
文摘Multiple sclerosis(MS)is a chronic disorder of the central nervous system characterized by multifocal lesions where inflammation,demyelination,and neurodegeneration occur(Jakimovski et al.,2024).MS diagnosis primarily relies on the demonstration of dissemination in time and space of the lesions based on clinical,magnetic resonance imaging(MRI),and cerebrospinal fluid assessments(Jakimovski et al.,2024).
基金Deutsche Forschungsgemeinschaft(DFG,German Research Foundation),project numbers 324633948 and 409784463(DFG grants Hi 678/9-3 and Hi 678/10-2,FOR2953)to HHBundesministerium für Bildung und Forschung-BMBF,project number 16LW0463K to HT.
文摘Microglia are the resident macrophages of the central nervous system.They act as the first line of defense against pathogens and play essential roles in neuroinflammation and tissue repair after brain insult or in neurodegenerative and demyelinating diseases(Borst et al.,2021).Together with infiltrating monocyte-derived macrophages,microglia also play a critical role for brain tumor development,since immunosuppressive interactions between tumor cells and tumor-associated microglia and macrophages(TAM)are linked to malignant progression.This mechanism is of particular relevance in glioblastoma(GB),the deadliest form of brain cancer with a median overall survival of less than 15 months(Khan et al.,2023).Therefore,targeting microglia and macrophage activation is a promising strategy for therapeutic interference in brain disease.
