Optogenetics is a combination of optics and genetics technology that can be used to activate or inhibit specific cells in tissues. It has been used to treat Parkinson’s disease, epilepsy and neurological diseases, bu...Optogenetics is a combination of optics and genetics technology that can be used to activate or inhibit specific cells in tissues. It has been used to treat Parkinson’s disease, epilepsy and neurological diseases, but rarely Alzheimer’s disease. Adeno-associated virus carrying the CaMK promoter driving the optogenetic channelrhodopsin-2 (CHR2) gene (or without the CHR2 gene, as control) was injected into the bilateral dentate gyri, followed by repeated intrahippocampal injections of soluble low-molecular-weight amyloid-β1–42 peptide (Aβ1–42). Subsequently, the region was stimulated with a 473 nm laser (1–3 ms, 10 Hz, 5 minutes). The novel object recognition test was conducted to test memory function in mice. Immunohistochemical staining was performed to analyze the numbers of NeuN and synapsin Ia/b-positive cells in the hippocampus. Western blot assay was carried out to analyze the expression levels of glial fibrillary acidic protein, NeuN, synapsin Ia/b, metabotropic glutamate receptor-1a (mGluR-1a), mGluR-5, N-methyl-D-aspartate receptor subunit NR1, glutamate receptor 2, interleukin-1β, interleukin-6 and interleukin-10. Optogenetic stimulation improved working and short-term memory in mice with Alzheimer’s disease. This neuroprotective effect was associated with increased expression of NR1, glutamate receptor 2 and mGluR-5 in the hippocampus, and decreased expression of glial fibrillary acidic protein and interleukin-6. Our results show that optogenetics can be used to regulate the neuronal-glial network to ameliorate memory functions in mice with Alzheimer’s disease. The study was approved by the Animal Resources Committee of Jinan University, China (approval No. LL-KT-2011134) on February 28, 2011.展开更多
In tauopathies,memory impairment positively strongly correlates with the amount of abnormal tau aggregates;however,how tau accumulation induces synapse impairment is unclear.Recently,we found that human tau accumulati...In tauopathies,memory impairment positively strongly correlates with the amount of abnormal tau aggregates;however,how tau accumulation induces synapse impairment is unclear.Recently,we found that human tau accumulation activated Signal Transduction and Activator of Transcription-1(STAT1)to inhibit the transcription of synaptic N-methyl-D-aspartate receptors(NMDARs).Here,overexpressing human P301L mutant tau(P301L-hTau)increased the phosphorylated level of Signal Transduction and Activator of Transcription-3(STAT3)at Tyr705 by JAK2,which would promote STAT3 translocate into the nucleus and activate STAT3.However,STAT3 was found mainly located in the cytoplasm.Further study found that P301L-htau acetylated STAT1 to bind with STAT3 in the cytoplasm,and thus inhibited the nuclear translocation and inactivation of STAT3.Knockdown of STAT3 in STAT3flox/flox mice mimicked P301L-hTau-induced suppression of NMDARs expression,synaptic and memory impairments.Overexpressing STAT3 rescued P301L-hTau-induced synaptic and cognitive deficits by increasing NMDARs expression.Further study proved that STAT3 positively regulated NMDARs transcription through direct binding to the specific GAS element of NMDARs promoters.These findings indicate that accumulated P301L-hTau inactivating STAT3 to suppress NMDARs expression,revealed a novel mechanism for tau-associated synapse and cognition deficits,and STAT3 will hopefully serve as a potential pharmacological target for tauopathies treatment.展开更多
In tauopathies,memory impairment positively strongly correlates with the amount of abnormal tau aggregates;however,how tau accumulation induces synapse impairment is unclear.Recently,we found that human tau accumulati...In tauopathies,memory impairment positively strongly correlates with the amount of abnormal tau aggregates;however,how tau accumulation induces synapse impairment is unclear.Recently,we found that human tau accumulation activated Signal Transduction and Activator of Transcription-1(STAT1)to inhibit the transcription of synaptic N-methyl-D-aspartate receptors(NMDARs).Here,overexpressing human P301L mutant tau(P301L-hTau)increased the phosphorylated level of Signal Transduction and Activator of Transcription-3(STAT3)at Tyr705 by JAK2,which would promote STAT3 translocate into the nucleus and activate STAT3.However,STAT3 was found mainly located in the cytoplasm.Further study found that P301L-htau acetylated STAT1 to bind with STAT3 in the cytoplasm,and thus inhibited the nuclear translocation and inactivation of STAT3.Knockdown of STAT3 in STAT3^(flox/flox) mice mimicked P301L-hTau-induced suppression of NMDARs expression,synaptic and memory impairments.Overexpressing STAT3 rescued P301L-hTau-induced synaptic and cognitive deficits by increasing NMDARs expression.Further study proved that STAT3 positively regulated NMDARs transcription through direct binding to the specific GAS element of NMDARs promoters.These findings indicate that accumulated P301L-hTau inactivating STAT3 to suppress NMDARs expression,revealed a novel mechanism for tau-associated synapse and cognition deficits,and STAT3 will hopefully serve as a potential pharmacological target for tauopathies treatment.展开更多
基金supported by the National Natural Science Foundation of China,No.81171191(to LYZ)the Shenzhen Special Fund Project on Strategic Emerging Industry Development of China,No.JCYJ20160422170522075(to LYZ)the Shenzhen Healthcare Research Project of China,No.201601015(to LYZ)
文摘Optogenetics is a combination of optics and genetics technology that can be used to activate or inhibit specific cells in tissues. It has been used to treat Parkinson’s disease, epilepsy and neurological diseases, but rarely Alzheimer’s disease. Adeno-associated virus carrying the CaMK promoter driving the optogenetic channelrhodopsin-2 (CHR2) gene (or without the CHR2 gene, as control) was injected into the bilateral dentate gyri, followed by repeated intrahippocampal injections of soluble low-molecular-weight amyloid-β1–42 peptide (Aβ1–42). Subsequently, the region was stimulated with a 473 nm laser (1–3 ms, 10 Hz, 5 minutes). The novel object recognition test was conducted to test memory function in mice. Immunohistochemical staining was performed to analyze the numbers of NeuN and synapsin Ia/b-positive cells in the hippocampus. Western blot assay was carried out to analyze the expression levels of glial fibrillary acidic protein, NeuN, synapsin Ia/b, metabotropic glutamate receptor-1a (mGluR-1a), mGluR-5, N-methyl-D-aspartate receptor subunit NR1, glutamate receptor 2, interleukin-1β, interleukin-6 and interleukin-10. Optogenetic stimulation improved working and short-term memory in mice with Alzheimer’s disease. This neuroprotective effect was associated with increased expression of NR1, glutamate receptor 2 and mGluR-5 in the hippocampus, and decreased expression of glial fibrillary acidic protein and interleukin-6. Our results show that optogenetics can be used to regulate the neuronal-glial network to ameliorate memory functions in mice with Alzheimer’s disease. The study was approved by the Animal Resources Committee of Jinan University, China (approval No. LL-KT-2011134) on February 28, 2011.
基金supported in parts by Natural Science Foundation of China(81870846)the Ministry of Science and Technology of China(2016YFC13058001)Sanming Project of Medicine in Shenzhen(SZSM201611090).
文摘In tauopathies,memory impairment positively strongly correlates with the amount of abnormal tau aggregates;however,how tau accumulation induces synapse impairment is unclear.Recently,we found that human tau accumulation activated Signal Transduction and Activator of Transcription-1(STAT1)to inhibit the transcription of synaptic N-methyl-D-aspartate receptors(NMDARs).Here,overexpressing human P301L mutant tau(P301L-hTau)increased the phosphorylated level of Signal Transduction and Activator of Transcription-3(STAT3)at Tyr705 by JAK2,which would promote STAT3 translocate into the nucleus and activate STAT3.However,STAT3 was found mainly located in the cytoplasm.Further study found that P301L-htau acetylated STAT1 to bind with STAT3 in the cytoplasm,and thus inhibited the nuclear translocation and inactivation of STAT3.Knockdown of STAT3 in STAT3flox/flox mice mimicked P301L-hTau-induced suppression of NMDARs expression,synaptic and memory impairments.Overexpressing STAT3 rescued P301L-hTau-induced synaptic and cognitive deficits by increasing NMDARs expression.Further study proved that STAT3 positively regulated NMDARs transcription through direct binding to the specific GAS element of NMDARs promoters.These findings indicate that accumulated P301L-hTau inactivating STAT3 to suppress NMDARs expression,revealed a novel mechanism for tau-associated synapse and cognition deficits,and STAT3 will hopefully serve as a potential pharmacological target for tauopathies treatment.
基金This work was supported in parts by Natural Science Foundation of China(81870846)the Ministry of Science and Technology of China(2016YFC13058001)Sanming Project of Medicine in Shenzhen(SZSM201611090).
文摘In tauopathies,memory impairment positively strongly correlates with the amount of abnormal tau aggregates;however,how tau accumulation induces synapse impairment is unclear.Recently,we found that human tau accumulation activated Signal Transduction and Activator of Transcription-1(STAT1)to inhibit the transcription of synaptic N-methyl-D-aspartate receptors(NMDARs).Here,overexpressing human P301L mutant tau(P301L-hTau)increased the phosphorylated level of Signal Transduction and Activator of Transcription-3(STAT3)at Tyr705 by JAK2,which would promote STAT3 translocate into the nucleus and activate STAT3.However,STAT3 was found mainly located in the cytoplasm.Further study found that P301L-htau acetylated STAT1 to bind with STAT3 in the cytoplasm,and thus inhibited the nuclear translocation and inactivation of STAT3.Knockdown of STAT3 in STAT3^(flox/flox) mice mimicked P301L-hTau-induced suppression of NMDARs expression,synaptic and memory impairments.Overexpressing STAT3 rescued P301L-hTau-induced synaptic and cognitive deficits by increasing NMDARs expression.Further study proved that STAT3 positively regulated NMDARs transcription through direct binding to the specific GAS element of NMDARs promoters.These findings indicate that accumulated P301L-hTau inactivating STAT3 to suppress NMDARs expression,revealed a novel mechanism for tau-associated synapse and cognition deficits,and STAT3 will hopefully serve as a potential pharmacological target for tauopathies treatment.
