Background Deoxyribonuclease 2(DNaseⅡ)plays a key role in clearing cytoplasmic double-stranded DNA(dsDNA).Deficiency of DNaseⅡleads to DNA accumulation in the cytoplasm.Persistent dsDNA in neurons is an early pathol...Background Deoxyribonuclease 2(DNaseⅡ)plays a key role in clearing cytoplasmic double-stranded DNA(dsDNA).Deficiency of DNaseⅡleads to DNA accumulation in the cytoplasm.Persistent dsDNA in neurons is an early pathological hallmark of senescence and neurodegenerative diseases including Alzheimer’s disease(AD).However,it is not clear how DNaseⅡand neuronal cytoplasmic dsDNA influence neuropathogenesis.Tau hyperphosphorylation is a key factor for the pathogenesis of AD.The effect of DNaseⅡand neuronal cytoplasmic dsDNA on neuronal tau hyperphosphorylation remains unclarified.Methods The levels of neuronal DNaseⅡand dsDNA in WT and Tau-P301S mice of different ages were measured by immunohistochemistry and immunolabeling,and the levels of DNaseⅡin the plasma of AD patients were measured by ELISA.To investigate the impact of DNaseⅡon tauopathy,the levels of phosphorylated tau,phosphokinase,phosphatase,synaptic proteins,gliosis and proinflammatory cytokines in the brains of neuronal DNaseⅡ-deficient WT mice,neuronal DNaseⅡ-deficient Tau-P301S mice and neuronal DNaseⅡ-overexpressing Tau-P301S mice were evaluated by immunolabeling,immunoblotting or ELISA.Cognitive performance was determined using the Morris water maze test,Y-maze test,novel object recognition test and open field test.Results The levels of DNaseⅡwere significantly decreased in the brains and the plasma of AD patients.DNaseⅡalso decreased age-dependently in the neurons of WT and Tau-P301S mice,along with increased dsDNA accumulation in the cytoplasm.The DNA accumulation induced by neuronal DNaseⅡdeficiency drove tau phosphorylation by upregulating cyclin-dependent-like kinase-5(CDK5)and calcium/calmodulin activated protein kinaseⅡ(CaMKⅡ)and downregulating phosphatase protein phosphatase 2A(PP2A).Moreover,DNaseⅡknockdown induced and significantly exacerbated neuron loss,neuroinflammation and cognitive deficits in WT and Tau-P301S mice,respectively,while overexpression of neuronal DNaseⅡexhibited therapeutic benefits.Conclusions DNaseⅡdeficiency and cytoplasmic dsDNA accumulation can initiate tau phosphorylation,suggesting DNaseⅡas a potential therapeutic target for tau-associated disorders.展开更多
基金supported by funding from the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB39050600)the National Natural Science Foundation of China(82150107 and 81971073)the National Key Research and Development Program of China(2020YFA0712402).
文摘Background Deoxyribonuclease 2(DNaseⅡ)plays a key role in clearing cytoplasmic double-stranded DNA(dsDNA).Deficiency of DNaseⅡleads to DNA accumulation in the cytoplasm.Persistent dsDNA in neurons is an early pathological hallmark of senescence and neurodegenerative diseases including Alzheimer’s disease(AD).However,it is not clear how DNaseⅡand neuronal cytoplasmic dsDNA influence neuropathogenesis.Tau hyperphosphorylation is a key factor for the pathogenesis of AD.The effect of DNaseⅡand neuronal cytoplasmic dsDNA on neuronal tau hyperphosphorylation remains unclarified.Methods The levels of neuronal DNaseⅡand dsDNA in WT and Tau-P301S mice of different ages were measured by immunohistochemistry and immunolabeling,and the levels of DNaseⅡin the plasma of AD patients were measured by ELISA.To investigate the impact of DNaseⅡon tauopathy,the levels of phosphorylated tau,phosphokinase,phosphatase,synaptic proteins,gliosis and proinflammatory cytokines in the brains of neuronal DNaseⅡ-deficient WT mice,neuronal DNaseⅡ-deficient Tau-P301S mice and neuronal DNaseⅡ-overexpressing Tau-P301S mice were evaluated by immunolabeling,immunoblotting or ELISA.Cognitive performance was determined using the Morris water maze test,Y-maze test,novel object recognition test and open field test.Results The levels of DNaseⅡwere significantly decreased in the brains and the plasma of AD patients.DNaseⅡalso decreased age-dependently in the neurons of WT and Tau-P301S mice,along with increased dsDNA accumulation in the cytoplasm.The DNA accumulation induced by neuronal DNaseⅡdeficiency drove tau phosphorylation by upregulating cyclin-dependent-like kinase-5(CDK5)and calcium/calmodulin activated protein kinaseⅡ(CaMKⅡ)and downregulating phosphatase protein phosphatase 2A(PP2A).Moreover,DNaseⅡknockdown induced and significantly exacerbated neuron loss,neuroinflammation and cognitive deficits in WT and Tau-P301S mice,respectively,while overexpression of neuronal DNaseⅡexhibited therapeutic benefits.Conclusions DNaseⅡdeficiency and cytoplasmic dsDNA accumulation can initiate tau phosphorylation,suggesting DNaseⅡas a potential therapeutic target for tau-associated disorders.
