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
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.
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.
基金National Natural Science Foundation of China(No.81860278)Basic Research Project of Science and Technology Department of Yunnan Province,China(No.202201AT070197)。
