Objective Chronic stress can induce cognitive dysfunction,but the underlying mechanisms remain unknown.Studies have confirmed that the high mobility group box 1/Toll-like receptor 4(HMGB1/TLR4)pathway is closely assoc...Objective Chronic stress can induce cognitive dysfunction,but the underlying mechanisms remain unknown.Studies have confirmed that the high mobility group box 1/Toll-like receptor 4(HMGB1/TLR4)pathway is closely associated with cognitive impairment.Therefore,this research aimed to explore whether the HMGB1/TLR4 pathway involves in chronic stress-induced cognitive dysfunction.Methods The chronic unpredictable mild stress(CUMS)mouse model was established by randomly giving different types of stress every day for four consecutive weeks.Cognitive function was detected by novel object recognition test,Y-maze test,and Morris water maze test.The protein expressions of HMGB1,TLR4,B-cell lymphoma 2(BCL2),and BCL2 associated X(BAX)were determined by Western blot.The damage of neurons in the hippocampal CA1 region was observed by hematoxylin-eosin(HE)staining.Results The protein expressions of HMGB1 and TLR4 were significantly increased in the hippocampus of chronic stress mice.Furthermore,inhibition of the HMGB1/TLR4 pathway induced by ethyl pyruvate(EP,a specific inhibitor of HMGB1)and TAK242(a selective inhibitor of TLR4)treatment attenuated cognitive impairment in chronic stress mice,according to the novel object recognition test,Y-maze test,and Morris water maze test.In addition,administration of EP and TAK242 also mitigated the increase of apoptosis in the hippocampus of chronic stress mice.Conclusion These results indicate that the hippocampal HMGB1/TLR4 pathway contributes to chronic stress-induced apoptosis and cognitive dysfunction.展开更多
OBJECTIVE A causal relationshiphas been postulated between cholinergic dysfunction and the progression of cognitive decline in neurodegenerative disorders. However,the cause of the cognitive dysfunction remains unclea...OBJECTIVE A causal relationshiphas been postulated between cholinergic dysfunction and the progression of cognitive decline in neurodegenerative disorders. However,the cause of the cognitive dysfunction remains unclear. METHODS Gab1^(loxP/loxP) were bred with ChAT-Cre mice to generate ChAT-Cre; Gab1^(f/f) mice. Excitability of cholinergic neurons wererecorded using whole-cel patch clump. A series of behavioral analyses were used to address the changes of cognitive function in ChAT-Cre; Gab1^(f/f) mice. Neurochemical changes on brain of conditional knockout mice were evaluated by using immunohistochemistry and Western blotting analysis. RESULTS Grb2-associated-binding protein 1(Gab1) is adocking/scaffolding molecule known to play an important role in cell growth and survival. Here,wereport that Gab1 is decreased in cholinergic neurons in a mousemodel of AD. We found that selective downregulation of Gab1 in the septum impaired learning and memory and hippocampal long-term potentiation,whereas overexpression of Gab1 in the same area rescued the cognitive deficitsseen in ChAT-Cre; Gab1^(f/f) and APP^(swe)/PS1 mice.^(18)F-FDGmicroP ET imaging data indicated that Gab1 treatment had no effect on metabolic activity of glucose in APPswe/PS1 mice. Moreover,we identify abnormal function of SKchannelscontributes to increased firing in cholinergic neuronsof ChAT-Cre; Gab1^(f/f) mice. CONCLUSION Gab1 signaling may serve as a potential treatment target for neurological disorders involving dysfunction of central cholinergic neurons.展开更多
OBJECTIVE To investigate the effects of Huanglian Jiedu decoction on cognitive dysfunction of zebrafish with Alzheimer disease.METHODS 126 g of coptis chinensis,84 g of phellorescent phellorescent chinensis,84 g of sc...OBJECTIVE To investigate the effects of Huanglian Jiedu decoction on cognitive dysfunction of zebrafish with Alzheimer disease.METHODS 126 g of coptis chinensis,84 g of phellorescent phellorescent chinensis,84 g of scutellaria chinensis and 126 g of gardenia chinensis were immersed in 10,8 and 8 times of water for 30 min,and then extracted at 100℃for 2,1.5 and 1.5 h,respectively.The three extracts were coarse filtered and concentrated into 308 g·L-1 and stored in refrigerator for later use.200 zebrafish were selected for behavioral train⁃ing in T-shaped tank for seven days.After that,the behavioral record analysis software Smart 3.0 was used to conduct behavioral analysis.Qualified zebrafish were selected as the blank group.Except for the blank group,zebrafish in the other 5 groups were exposed to AlCl3100μg·L-1 aquaculture water for modeling,and exposed for 6 d.The behavioral record analysis software Smart 3.0 was used to conduct behavioral analysis,and Select the successfully modeled zebraf⁃ish.After that,huperzine A(4μg·L-1)and Huan⁃glian Jiedu decoction of low,medium and high doses(154,308 and 616 mg·L-1)were adminis⁃tered respectively,and exposed for six days.Then,the behavior analysis was conducted again through the behavioral record analysis soft⁃ware Smart 3.0 to select qualified zebrafish.After the training,the brain and gut of zebrafish in each group were collected,and the expression changes of N-cadherin,p-P38/p38MAPK and p-Tau in the brain were detected by Western blot⁃ting and qPCR to show the effect of Huanglian Jiedu decoction on cognitive dysfunction of Zebrafish with Alzheimer disease.RESULTS Western blotting and qPCR results showed that the contents of N-cadherin increased(P<0.05),and the contents of p-P38/p38MAPK and p-Tau decreased(P<0.05)compared with the model group,indicating that Huanglian Jiadu decoction had an effect on the cognitive dysfunction of zebrafish with Alzheimer disease.CONCLU⁃SION Huanglian Jiedu decoction can alleviate cognitive dysfunction of zebrafish model with Alzheimer disease to a certain extent.展开更多
文摘Objective Chronic stress can induce cognitive dysfunction,but the underlying mechanisms remain unknown.Studies have confirmed that the high mobility group box 1/Toll-like receptor 4(HMGB1/TLR4)pathway is closely associated with cognitive impairment.Therefore,this research aimed to explore whether the HMGB1/TLR4 pathway involves in chronic stress-induced cognitive dysfunction.Methods The chronic unpredictable mild stress(CUMS)mouse model was established by randomly giving different types of stress every day for four consecutive weeks.Cognitive function was detected by novel object recognition test,Y-maze test,and Morris water maze test.The protein expressions of HMGB1,TLR4,B-cell lymphoma 2(BCL2),and BCL2 associated X(BAX)were determined by Western blot.The damage of neurons in the hippocampal CA1 region was observed by hematoxylin-eosin(HE)staining.Results The protein expressions of HMGB1 and TLR4 were significantly increased in the hippocampus of chronic stress mice.Furthermore,inhibition of the HMGB1/TLR4 pathway induced by ethyl pyruvate(EP,a specific inhibitor of HMGB1)and TAK242(a selective inhibitor of TLR4)treatment attenuated cognitive impairment in chronic stress mice,according to the novel object recognition test,Y-maze test,and Morris water maze test.In addition,administration of EP and TAK242 also mitigated the increase of apoptosis in the hippocampus of chronic stress mice.Conclusion These results indicate that the hippocampal HMGB1/TLR4 pathway contributes to chronic stress-induced apoptosis and cognitive dysfunction.
文摘OBJECTIVE A causal relationshiphas been postulated between cholinergic dysfunction and the progression of cognitive decline in neurodegenerative disorders. However,the cause of the cognitive dysfunction remains unclear. METHODS Gab1^(loxP/loxP) were bred with ChAT-Cre mice to generate ChAT-Cre; Gab1^(f/f) mice. Excitability of cholinergic neurons wererecorded using whole-cel patch clump. A series of behavioral analyses were used to address the changes of cognitive function in ChAT-Cre; Gab1^(f/f) mice. Neurochemical changes on brain of conditional knockout mice were evaluated by using immunohistochemistry and Western blotting analysis. RESULTS Grb2-associated-binding protein 1(Gab1) is adocking/scaffolding molecule known to play an important role in cell growth and survival. Here,wereport that Gab1 is decreased in cholinergic neurons in a mousemodel of AD. We found that selective downregulation of Gab1 in the septum impaired learning and memory and hippocampal long-term potentiation,whereas overexpression of Gab1 in the same area rescued the cognitive deficitsseen in ChAT-Cre; Gab1^(f/f) and APP^(swe)/PS1 mice.^(18)F-FDGmicroP ET imaging data indicated that Gab1 treatment had no effect on metabolic activity of glucose in APPswe/PS1 mice. Moreover,we identify abnormal function of SKchannelscontributes to increased firing in cholinergic neuronsof ChAT-Cre; Gab1^(f/f) mice. CONCLUSION Gab1 signaling may serve as a potential treatment target for neurological disorders involving dysfunction of central cholinergic neurons.
基金National Natural Science Foundation of china(8216140711)Natural Science Foundation of Guangxi Province(2017GXNSFAA198255)+2 种基金Natural Science Foun⁃dation of Guangxi Province(2018GXNSFBA138028)Open Project Program of Guangxi Key Laboratory of Brain and Cognitive Neuroscience,GuilinMedicalUniversity(GKLBCN-20180105-03)and 2019 College Student Innovation and Entre⁃preneurship Project Training Program(201910601038)。
文摘OBJECTIVE To investigate the effects of Huanglian Jiedu decoction on cognitive dysfunction of zebrafish with Alzheimer disease.METHODS 126 g of coptis chinensis,84 g of phellorescent phellorescent chinensis,84 g of scutellaria chinensis and 126 g of gardenia chinensis were immersed in 10,8 and 8 times of water for 30 min,and then extracted at 100℃for 2,1.5 and 1.5 h,respectively.The three extracts were coarse filtered and concentrated into 308 g·L-1 and stored in refrigerator for later use.200 zebrafish were selected for behavioral train⁃ing in T-shaped tank for seven days.After that,the behavioral record analysis software Smart 3.0 was used to conduct behavioral analysis.Qualified zebrafish were selected as the blank group.Except for the blank group,zebrafish in the other 5 groups were exposed to AlCl3100μg·L-1 aquaculture water for modeling,and exposed for 6 d.The behavioral record analysis software Smart 3.0 was used to conduct behavioral analysis,and Select the successfully modeled zebraf⁃ish.After that,huperzine A(4μg·L-1)and Huan⁃glian Jiedu decoction of low,medium and high doses(154,308 and 616 mg·L-1)were adminis⁃tered respectively,and exposed for six days.Then,the behavior analysis was conducted again through the behavioral record analysis soft⁃ware Smart 3.0 to select qualified zebrafish.After the training,the brain and gut of zebrafish in each group were collected,and the expression changes of N-cadherin,p-P38/p38MAPK and p-Tau in the brain were detected by Western blot⁃ting and qPCR to show the effect of Huanglian Jiedu decoction on cognitive dysfunction of Zebrafish with Alzheimer disease.RESULTS Western blotting and qPCR results showed that the contents of N-cadherin increased(P<0.05),and the contents of p-P38/p38MAPK and p-Tau decreased(P<0.05)compared with the model group,indicating that Huanglian Jiadu decoction had an effect on the cognitive dysfunction of zebrafish with Alzheimer disease.CONCLU⁃SION Huanglian Jiedu decoction can alleviate cognitive dysfunction of zebrafish model with Alzheimer disease to a certain extent.
