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
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
Tau plays a crucial role in several neurodegenerative diseases,collectively referred to as tauopathies.Therefore,targeting potential pathological changes in tau could enable useful therapeutic interventions.However,ta...Tau plays a crucial role in several neurodegenerative diseases,collectively referred to as tauopathies.Therefore,targeting potential pathological changes in tau could enable useful therapeutic interventions.However,tau is not an easy target because it dynamically interacts with microtubules and other cellular components,which presents a challenge for tau-targeted drugs.New cellular models could aid the development of mechanism-based tau-targeted therapies.展开更多
Hans Zempel1,2 TAU,a microtubule-associated protein,encoded by the microtubule-associated protein tau(MAPT)gene,is a central regulator of microtubule stability and axonal function in the human brain,with its pathologi...Hans Zempel1,2 TAU,a microtubule-associated protein,encoded by the microtubule-associated protein tau(MAPT)gene,is a central regulator of microtubule stability and axonal function in the human brain,with its pathological aggregation representing a hallmark of Alzheimer’s disease and related tauopathies.Despite extensive research into the role of TAU in neurodegeneration,its essentiality for human brain development has remained unclear.This perspective synthesizes recent genetic,molecular,and cellular evidence to demonstrate that the human brain-specific TAU isoform 0N3R is indispensable for proper neurodevelopment,pointing to loss-of-function of this isoform as a novel paradigm for TAU-associated disease.Alternative splicing of MAPT generates six brain-specific TAU isoforms,with 0N3R being exclusively expressed during fetal brain development.Analysis of large-scale human genetic datasets(gnomAD v4.0.0)reveals a high probability of loss-of-function intolerance(pLI=0.96)for the 0N3R isoform.This is in stark contrast to the canonical Matched Annotation from the NCBI and EMBL-EBI(MANE)transcript and peripheral“Big TAU,”both of which are tolerant to loss-of-function mutations.This intolerance is further supported by the scarcity of loss-of-function mutations in 0N3R-encoding exons and high missense constraint scores,suggesting strong evolutionary selection against disruption of this isoform.Functional studies using human induced pluripotent stem cell-derived cortical neurons with CRISPR-Cas9-mediated MAPT knockout reveal that,unlike in murine models where compensation by other microtubule-associated proteins occurs,loss of TAU in human neurons leads to deficits in neurite outgrowth,axon initial segment shortening,and a trend toward hyperexcitability,accompanied by broad transcriptomic changes affecting genes involved in microtubule organization and synaptic structure.Remarkably,re-expression of any of the six human brain-specific TAU isoforms rescues these phenotypes,underscoring their functional redundancy during development.These findings position the 0N3R isoform as essential for human brain development and suggest that loss-of-function mutations affecting this isoform likely result in neurodevelopmental impairment,potentially manifesting as intellectual disability without overt dysmorphic features.This contrasts with the apparent tolerance to MAPT loss-of-function in mice and peripheral tissues,highlighting a critical species-and isoform-specific requirement for TAU in human neurodevelopment.The hypothesis of 0N3R-TAU loss-of-function intolerance opens new avenues for understanding neurodevelopmental disorders and refines the conceptual framework of TAU-associated disease mechanisms beyond toxic gain-of-function.展开更多
Sepsis-associated encephalopathy(SAE)is a severe neurological syndrome marked by widespread brain dysfunctions due to sepsis,yet the underlying mechanisms remain elusive.The current study,using a Lipopolysaccharide(LP...Sepsis-associated encephalopathy(SAE)is a severe neurological syndrome marked by widespread brain dysfunctions due to sepsis,yet the underlying mechanisms remain elusive.The current study,using a Lipopolysaccharide(LPS)-induced septic rat model,revealed the hyperphosphorylation of tau and cognitive impairments,accompanied by the release of inflammatory cytokines and activation of glial cells in the hippocampal dentate gyrus region of septic rats.Proteomic and bioinformatic analyses identified C-X-C motif chemokine ligand 10(CXCL10)as a central regulator of neuroinflammation.LPS triggered CXCL10 secretion in astrocytes,and astrocyte-conditioned medium from LPS-treated astrocytes induced tau hyperphosphorylation and synaptic deficits.Recombinant CXCL10 recapitulated these effects in vitro and in vivo.Blocking CXCL10–CXCR3 interaction reversed tau phosphorylation,synaptic impairment,and cognitive decline.Mechanistically,CXCL10–CXCR3 interaction activated CaMKII,driving tau hyperphosphorylation,while CaMKII inhibition restored synaptic protein levels.These findings establish CXCL10 as a key driver of tau pathology in SAE and suggest CXCL10–CXCR3 as a therapeutic target for sepsis-induced cognitive impairments.展开更多
Alzheimer’s disease,a devastating neurodegenerative disorder,is characterized by progressive cognitive decline,primarily due to amyloid-beta protein deposition and tau protein phosphorylation.Effectively reducing the...Alzheimer’s disease,a devastating neurodegenerative disorder,is characterized by progressive cognitive decline,primarily due to amyloid-beta protein deposition and tau protein phosphorylation.Effectively reducing the cytotoxicity of amyloid-beta42 aggregates and tau oligomers may help slow the progression of Alzheimer’s disease.Conventional drugs,such as donepezil,can only alleviate symptoms and are not able to prevent the underlying pathological processes or cognitive decline.Currently,active and passive immunotherapies targeting amyloid-beta and tau have shown some efficacy in mice with asymptomatic Alzheimer’s disease and other transgenic animal models,attracting considerable attention.However,the clinical application of these immunotherapies demonstrated only limited efficacy before the discovery of lecanemab and donanemab.This review first discusses the advancements in the pathogenesis of Alzheimer’s disease and active and passive immunotherapies targeting amyloid-beta and tau proteins.Furthermore,it reviews the advantages and disadvantages of various immunotherapies and considers their future prospects.Although some antibodies have shown promise in patients with mild Alzheimer’s disease,substantial clinical data are still lacking to validate their effectiveness in individuals with moderate Alzheimer’s disease.展开更多
BCL2-associated anthanogene 3 facilitates the clearance of tau protein aggregates:BCL2-associated anthanogene 3(BAG3)is a ubiquitously expressed and highly conserved multi-functional co-chaperone protein involved in m...BCL2-associated anthanogene 3 facilitates the clearance of tau protein aggregates:BCL2-associated anthanogene 3(BAG3)is a ubiquitously expressed and highly conserved multi-functional co-chaperone protein involved in many biological processes that supports cellular homeostasis,including the inhibition of apoptosis by preventing mitochondrial BAX localization(Lin et al.,2022)and the promotion of the degradation of hyperphosphorylated tau aggregates by its interactions with SQSTM1(p62)(Hamano and Mutoh,2022).展开更多
Alzheimer’s disease(AD)remains an incurable neurodegenerative disorder with devastating societal and personal impacts.Despite decades of intensive research,therapeutic efforts targeting the clinical stages of AD have...Alzheimer’s disease(AD)remains an incurable neurodegenerative disorder with devastating societal and personal impacts.Despite decades of intensive research,therapeutic efforts targeting the clinical stages of AD have largely failed to halt or reverse disease progression.This has prompted a critical shift in focus toward the earlier,preclinical stages of AD,where interventions may hold greater promise for altering the disease trajectory.展开更多
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.
文摘Tau plays a crucial role in several neurodegenerative diseases,collectively referred to as tauopathies.Therefore,targeting potential pathological changes in tau could enable useful therapeutic interventions.However,tau is not an easy target because it dynamically interacts with microtubules and other cellular components,which presents a challenge for tau-targeted drugs.New cellular models could aid the development of mechanism-based tau-targeted therapies.
文摘Hans Zempel1,2 TAU,a microtubule-associated protein,encoded by the microtubule-associated protein tau(MAPT)gene,is a central regulator of microtubule stability and axonal function in the human brain,with its pathological aggregation representing a hallmark of Alzheimer’s disease and related tauopathies.Despite extensive research into the role of TAU in neurodegeneration,its essentiality for human brain development has remained unclear.This perspective synthesizes recent genetic,molecular,and cellular evidence to demonstrate that the human brain-specific TAU isoform 0N3R is indispensable for proper neurodevelopment,pointing to loss-of-function of this isoform as a novel paradigm for TAU-associated disease.Alternative splicing of MAPT generates six brain-specific TAU isoforms,with 0N3R being exclusively expressed during fetal brain development.Analysis of large-scale human genetic datasets(gnomAD v4.0.0)reveals a high probability of loss-of-function intolerance(pLI=0.96)for the 0N3R isoform.This is in stark contrast to the canonical Matched Annotation from the NCBI and EMBL-EBI(MANE)transcript and peripheral“Big TAU,”both of which are tolerant to loss-of-function mutations.This intolerance is further supported by the scarcity of loss-of-function mutations in 0N3R-encoding exons and high missense constraint scores,suggesting strong evolutionary selection against disruption of this isoform.Functional studies using human induced pluripotent stem cell-derived cortical neurons with CRISPR-Cas9-mediated MAPT knockout reveal that,unlike in murine models where compensation by other microtubule-associated proteins occurs,loss of TAU in human neurons leads to deficits in neurite outgrowth,axon initial segment shortening,and a trend toward hyperexcitability,accompanied by broad transcriptomic changes affecting genes involved in microtubule organization and synaptic structure.Remarkably,re-expression of any of the six human brain-specific TAU isoforms rescues these phenotypes,underscoring their functional redundancy during development.These findings position the 0N3R isoform as essential for human brain development and suggest that loss-of-function mutations affecting this isoform likely result in neurodevelopmental impairment,potentially manifesting as intellectual disability without overt dysmorphic features.This contrasts with the apparent tolerance to MAPT loss-of-function in mice and peripheral tissues,highlighting a critical species-and isoform-specific requirement for TAU in human neurodevelopment.The hypothesis of 0N3R-TAU loss-of-function intolerance opens new avenues for understanding neurodevelopmental disorders and refines the conceptual framework of TAU-associated disease mechanisms beyond toxic gain-of-function.
基金supported by Grants from the National Natural Science Foundation of China(82330041 and 82201326)the China Postdoctoral Research Foundation(GZC20230898)the Science and Technology Innovation Team Project to Xiaochuan Wang from the Department of Science and Technology of Hubei Province(2022-72-18).
文摘Sepsis-associated encephalopathy(SAE)is a severe neurological syndrome marked by widespread brain dysfunctions due to sepsis,yet the underlying mechanisms remain elusive.The current study,using a Lipopolysaccharide(LPS)-induced septic rat model,revealed the hyperphosphorylation of tau and cognitive impairments,accompanied by the release of inflammatory cytokines and activation of glial cells in the hippocampal dentate gyrus region of septic rats.Proteomic and bioinformatic analyses identified C-X-C motif chemokine ligand 10(CXCL10)as a central regulator of neuroinflammation.LPS triggered CXCL10 secretion in astrocytes,and astrocyte-conditioned medium from LPS-treated astrocytes induced tau hyperphosphorylation and synaptic deficits.Recombinant CXCL10 recapitulated these effects in vitro and in vivo.Blocking CXCL10–CXCR3 interaction reversed tau phosphorylation,synaptic impairment,and cognitive decline.Mechanistically,CXCL10–CXCR3 interaction activated CaMKII,driving tau hyperphosphorylation,while CaMKII inhibition restored synaptic protein levels.These findings establish CXCL10 as a key driver of tau pathology in SAE and suggest CXCL10–CXCR3 as a therapeutic target for sepsis-induced cognitive impairments.
基金supported by the Nature Science Foundation of Liaoning Province,Nos.2022-MS-211,2021-MS-064,and 2024-MS-048(all to YC).
文摘Alzheimer’s disease,a devastating neurodegenerative disorder,is characterized by progressive cognitive decline,primarily due to amyloid-beta protein deposition and tau protein phosphorylation.Effectively reducing the cytotoxicity of amyloid-beta42 aggregates and tau oligomers may help slow the progression of Alzheimer’s disease.Conventional drugs,such as donepezil,can only alleviate symptoms and are not able to prevent the underlying pathological processes or cognitive decline.Currently,active and passive immunotherapies targeting amyloid-beta and tau have shown some efficacy in mice with asymptomatic Alzheimer’s disease and other transgenic animal models,attracting considerable attention.However,the clinical application of these immunotherapies demonstrated only limited efficacy before the discovery of lecanemab and donanemab.This review first discusses the advancements in the pathogenesis of Alzheimer’s disease and active and passive immunotherapies targeting amyloid-beta and tau proteins.Furthermore,it reviews the advantages and disadvantages of various immunotherapies and considers their future prospects.Although some antibodies have shown promise in patients with mild Alzheimer’s disease,substantial clinical data are still lacking to validate their effectiveness in individuals with moderate Alzheimer’s disease.
基金supported by the award W81XWH1910309 (to HF) from the Department of Defensethe award R01-AG075092-01 (to HF)+2 种基金the award RF1AG063521 from the National Institute of Aging at the National Institutes of Healththe Neurological Research Institute Seed grant (to HF) from The Ohio State Universitythe Summer Undergraduate Research Fellowship (to NS) from The Ohio State University Chronic Brain Injury Discovery Theme
文摘BCL2-associated anthanogene 3 facilitates the clearance of tau protein aggregates:BCL2-associated anthanogene 3(BAG3)is a ubiquitously expressed and highly conserved multi-functional co-chaperone protein involved in many biological processes that supports cellular homeostasis,including the inhibition of apoptosis by preventing mitochondrial BAX localization(Lin et al.,2022)and the promotion of the degradation of hyperphosphorylated tau aggregates by its interactions with SQSTM1(p62)(Hamano and Mutoh,2022).
基金supported by the Canadian Institutes of Health Research Project grant (PJT-169197) to QYsupported by a CGS-M fellowship from the Canadian Institutes of Health Research
文摘Alzheimer’s disease(AD)remains an incurable neurodegenerative disorder with devastating societal and personal impacts.Despite decades of intensive research,therapeutic efforts targeting the clinical stages of AD have largely failed to halt or reverse disease progression.This has prompted a critical shift in focus toward the earlier,preclinical stages of AD,where interventions may hold greater promise for altering the disease trajectory.
