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
Alzheimer’s disease(AD),also defined as a tauopathology,is a common neurodegenerative disease.Hyper-phosphorylation,cleavage or truncation,and aggregation of tau contribute to AD.Thus,targeting the post-translational...Alzheimer’s disease(AD),also defined as a tauopathology,is a common neurodegenerative disease.Hyper-phosphorylation,cleavage or truncation,and aggregation of tau contribute to AD.Thus,targeting the post-translational modifications on tau may be a therapeutic strategy to treat AD.This study understood how cornel iridoid glycoside(CIG)affects tau post-translational modifications and synaptic abnormalities.The 10-month old P301S tau transgenic mice were given CIG at 100 and 200 mg/kg every day orally for 1 month.Hyperphosphorylated and truncated tau,synapse-associated proteins and glutamatergic receptors were all detected using Western blotting.The interactions between Morroniside(MOR)or Loganin(LOG)and tau were detected using Autodock and Surface Plasmon Resonance(SPR).The effects of CIG on the aggregation of tau were investigated using a cell-free system.CIG attenuated tau hyperphosphorylation at Thr205,Ser212,Ser262,Thr231 and Ser235(AT180),but had no effect on tau truncation in the brains of 10-month old P301S mice.Binding free energies and interactions revealed that MOR and LOG bound with tau.We also found that CIG upregulated synapse-associated proteins such as PSD-95,syntaxin1A and synaptotagmin.In addition,CIG restored N-methyl-D-aspartic acid receptor and glutamate receptor levels.CIG improves post-translational modification of tau as well as synaptic abnormalities.The data presented here reveal that CIG may be used in the treatment of AD.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.
基金This project was supported by grants from National Natural Science Foundation of China(No.81874351 and No 81703729)Beijing Hospitals Authority Ascent Plan of China(No.DFL20190803)National Major Science and Technology Projects of China(No.2015ZX09101-016).
文摘Alzheimer’s disease(AD),also defined as a tauopathology,is a common neurodegenerative disease.Hyper-phosphorylation,cleavage or truncation,and aggregation of tau contribute to AD.Thus,targeting the post-translational modifications on tau may be a therapeutic strategy to treat AD.This study understood how cornel iridoid glycoside(CIG)affects tau post-translational modifications and synaptic abnormalities.The 10-month old P301S tau transgenic mice were given CIG at 100 and 200 mg/kg every day orally for 1 month.Hyperphosphorylated and truncated tau,synapse-associated proteins and glutamatergic receptors were all detected using Western blotting.The interactions between Morroniside(MOR)or Loganin(LOG)and tau were detected using Autodock and Surface Plasmon Resonance(SPR).The effects of CIG on the aggregation of tau were investigated using a cell-free system.CIG attenuated tau hyperphosphorylation at Thr205,Ser212,Ser262,Thr231 and Ser235(AT180),but had no effect on tau truncation in the brains of 10-month old P301S mice.Binding free energies and interactions revealed that MOR and LOG bound with tau.We also found that CIG upregulated synapse-associated proteins such as PSD-95,syntaxin1A and synaptotagmin.In addition,CIG restored N-methyl-D-aspartic acid receptor and glutamate receptor levels.CIG improves post-translational modification of tau as well as synaptic abnormalities.The data presented here reveal that CIG may be used in the treatment of AD.
