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Role of melatonin in Alzheimer-like neurodegeneration

Acta Pharmacologica Sinica 2006年第1期27卷 41-49页

作者： jian-zhi wang~(2,4) ze-fen wang~(2,3)2 pathophysiology department,key laboratory of neurological diseases of hubei province,tongji medical school,huazhong university of science and technology,wuhan 430030,china 3 department of Physiology,medical College,wuhan university wuhan 430071,china pathophysiologydepartment KeyLaboratoryofNeurologicalDiseasesofHubeiProvinceTongjiMedicalSchoolHuazhongUniversityoJScienceandTechnologyWuhan430030China departmentofPhysiology MedicalCollegeWuhanUniversityWuhan

Alzheimer disease (AD),an age-related neurodegenerative disorder with progres-sive loss of memory and deterioration of comprehensive cognition,is character-ized by extracellular senile plaques of aggregated β-amyloid (Aβ),and intracellularneurofibrillary tangles that contain hyperphosphorylated tau *** showed that melatonin,an indoleamine secreted by the pineal gland,mayplay an important role in aging and AD as an antioxidant and *** decreases during aging and patients with AD have a more profoundreduction in this *** from clinical trials indicate that melatonin supple-mentation improves sleep,ameliorates sundowning,and slows down the progres-sion of cognitive impairment in Alzheimer's *** efficiently pro-tects neuronal cells from Aβ-mediated toxicity via antioxidant and anti-amyloidproperties:it not only inhibits Aβ generation,but also arrests the formation ofamyloid fibrils by a structure-dependent interaction with Aβ.Our recent studieshave demonstrated that melatonin efficiently attenuates Alzheimer-like *** the exact mechanism is still not fully understood,a direct regulatory influence of melatonin on the activities of protein kinases andprotein phosphatases is ***,melatonin also plays a role inprotecting cholinergic neurons and in ***,the neuroprotectiveeffects of melatonin and the underlying mechanisms by which it exerts its effectsare *** capacity of melatonin to prevent or ameliorate tau and Aβpathology further enhances its potential in the prevention or treatment of AD.

关键词： Alzheimer disease melatonin tau,beta amyloid

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A positive feedback inhibition of isocitrate dehydrogenase 3β on paired-box gene 6 promotes Alzheimer-like pathology

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Signal Transduction and Targeted Therapy 2024年第5期9卷 2324-2340页

作者： Xin wang Qian Liu Hai-tao Yu Jia-zhao Xie Jun-ning Zhao zhi-ting Fang Min Qu Yao Zhang Ying Yang jian-zhi wang department of pathophysiology School of Basic MedicineKey Laboratory of Education Ministry of China/Hubei Province for Neurological DisordersTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina department of Fundamental Medicine Wuxi School of MedicineJiangnan UniversityWuxiJiangsu 214122China hubei Provincial key laboratory for Applied Toxicology Hubei Provincial Center for Disease Control and PreventionHubei Provincial Academy of Preventive MedicineWuhan 430000China Endocrine department of Liyuan Hospital Key Laboratory of Ministry of Education of China for Neurological DisordersTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430077China Co-innovation Center of Neuroregeneration Nantong UniversityNantong 226000China

Impaired brain glucose metabolism is an early indicator of Alzheimer’s disease(AD);however,the fundamental mechanism is *** this study,we found a substantial decline in isocitrate dehydrogenase 3β(IDH3β)levels,a critical tricarboxylic acid cycle enzyme,in AD patients and AD-transgenic mice’s *** investigations demonstrated that the knockdown of IDH3βinduced oxidation-phosphorylation uncoupling,leading to reduced energy metabolism and lactate *** resulting increased lactate,a source of lactyl,was found to promote histone lactylation,thereby enhancing the expression of paired-box gene 6(PAX6).As an inhibitory transcription factor of IDH3β,the elevated PAX6 in turn inhibited the expression of IDH3β,leading to tau hyperphosphorylation,synapse impairment,and learning and memory deficits resembling those seen in *** AD-transgenic mice,upregulating IDH3βand downregulating PAX6 were found to improve cognitive functioning and reverse AD-like ***,our data suggest that impaired oxidative phosphorylation accelerates AD progression via a positive feedback inhibition loop of IDH3β-lactate-PAX6-IDH3β.Breaking this loop by upregulating IDH3βor downregulating PAX6 attenuates AD neurodegeneration and cognitive impairments.

关键词： metabolism Alzheimer impaired

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Role of glycogen synathese kinase-3β in Alzheimer-like neurodegeneration

Role of glycogen synathese kinase-3β in Alzheimer-like neur...

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中国病理生理学会第九届全国代表大会及学术会议

作者： wang jian-zhi (department of pathophysiology,key laboratory of Education Committee on neurological Disorders,tongji medical College, huazhong university of science and technology,wuhan 430030,china)

＜正＞Hyperphosphorylated tau in the form of paired helical filament is the major protein component of neurofibrillary tangle,which is positively correlated with the degree of dementia in patients with Alzheimer disease（AD）,the most common cause of dementia in the *** of protein kinases or/and inhibition of protein phosphatases is responsible for tau *** various kinases,glycogen synathese kinase-3β（GSK-3β） is the most *** studies have demonstrated that the active

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Role of glycogen synathese kinase-3β in Alzheimer-like neurodegeneration

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中国病理生理杂志 2010年第A10期26卷 1947-1947页

作者： wang jian-zhi(department of pathophysiology,key laboratory of Education Committee on neurological Disorders,tongji medical College,huazhong university of science and technology,wuhan 430030,china)

Hyperphosphorylated tau in the form of paired helical filament is the major protein component of neurofibrillary tangle,which is positively correlated with the degree of dementia in patients with Alzheimer disease(AD),the most common cause of dementia in the *** of protein kinases or/and inhibition of protein phosphatases is responsible for tau *** various kinases,glycogen

关键词： glycogen tangle elderly paired positively filament helical synaptic intracellular Activation

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Biomarkers and drug targets of Alzheimer’s disease

Biomarkers and drug targets of Alzheimer’s disease

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中国神经科学学会第九届全国学术会议暨第五次会员代表大会

作者： jian-zhi wang pathophysiology department,key laboratory of the Chinese Education Ministry for neurological Disorders,tongji medical College,huazhong university of science and technology,wuhan 430030,china

＜正＞Alzheimer’s disease（AD） is the most common cause of dementia affecting 47%in the population at age over *** there are licensed treatments that can alleviate the symptoms of AD,the efficacious diseasemodifying treatments are still *** pathophysiological process of AD is believed to begin many years before the diagnosis of dementia and this long preclinical phase would provide opportunity for the *** for improving diagnosis are moving forward,but a better consensus is needed to elucidate the link between the pathological cascade of AD and the clinical *** on the prevailing scientific evidence to date,a panel of biological and neuroimaging biomarkers that support clinical diagnosis have been developed recently,but further work is needed to understand these better and to establish whether interventions can substantially lower these *** this seminar,we will provide an overview of recent evidence regarding the biomarkers or drug targets of *** these molecules are solely intended for research purposes and do not have any clinical implications at this time,we believe that these biomarkers can provide a common rubric to advance the preclinical studies of AD,and ultimately,aid the field in moving toward earlier intervention of AD when some disease-modifying therapies may be most efficacious.

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Correction:A positive feedback inhibition of isocitrate dehydrogenase 3β on paired-box gene 6 promotes Alzheimerlike pathology

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Signal Transduction and Targeted Therapy 2024年第8期9卷 3537-3540页

作者： Xin wang Qian Liu Hai-tao Yu Jia-zhao Xie Jun-ning Zhao zhi-ting Fang Min Qu Yao Zhang Ying Yang jian-zhi wang department of pathophysiology School of Basic Medicine Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders Tongji Medical College Huazhong University of Science and Technology Wuhan China department of Fundamental Medicine Wuxi School of Medicine Jiangnan University Wuxi Jiangsu 214122 China Co-innovation Center of Neuroregeneration Nantong University Nantong 226000 China hubei Provincial key laboratory for Applied Toxicology Hubei Provincial Center for Disease Control and Prevention Hubei Provincial Academy of Preventive Medicine Wuhan 430000 China Endocrine department of Liyuan Hospital key laboratory of Ministry of Education of china for neurological Disorders Tongji Medical College Huazhong University of Science and Technology Wuhan 430077 China

After online publication of the article',the authors noticed that,owing to authors'oversight in layer placement within the illustration,Golgi staining images representing both the 5xFAD group and,the 5xFAD+IDH3β_grou... 详细信息

关键词： illustration representing noticed

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Bip overexpression induces tau hyperphosphorylation in HEK293/tau cell

Bip overexpression induces tau hyperphosphorylation in HEK29...

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中国神经科学学会第九届全国学术会议暨第五次会员代表大会

作者： Zan-Chao LIU,jian-zhi wang~*,Qing TIAN~* department of Pathology and pathophysiology,key laboratory of neurological Disease of National Education Ministry and hubei province,tongji medical College,huazhong university of science and technology,wuhan 430030,china

＜正＞Objective Alzhermer’s disease（AD） is the most common neurodegenerative disease with the progressive cognitive impairment as the major clinical *** microtubule associated protein tau is the major component of intracellular neurofibrillary（NFTs）,which is positively correlated with the decline of learning and memory in AD *** upstream effectors leading to tau hyperphosphorylation are still not fully *** reticulum（ER） is responsible for the posttranslational processing of newly synthesized proteins and ensuring proper protein folding and *** of damages（such as oxidative stress） can induce ER stress,which has been shown activated in the AD *** level of Bip,an ER stress marker,was also shown in the temporal cortex and the hippocampus of AD patients compared with age-matched *** present study is to explore whether Bip overexpression could induce tau *** Plasmid of Bip with EGFP-N1 vector was constructed and transfected into HEK293/tau *** phosphorylation levels of tau protein and the activities of the key tau phosphorylation related protein kinase glycogen synthase kinase-3β（GSK-3β）,and the key protein phosphatase protein phosphatase 2A（PP2A）,were ***（1） Bip overexpression in HEK293/tau cell induced increased phosphorylation levels of tau at Ser214,Ser262,Ser396,Ser404,Thr205 and Thr231 epitopes.（2） The increased phosphorylation levels of GSK-3βat Tyr216 and decreased phosphorylation levels at Ser9 were observed（indicating GSK-3βactivation）.（3） The phosphorylation of PP2A catalytic subunit at Tyr307 had no significant change.（4） Additionally,we also found increased Bip enhanced the association of tau and GSK3βby *** All these data confirmed that overexpression of Bip could induce hyperphosphotylation of tau in vitro by activating GSK-3βand enhancing the association of tau and GSK3β.

关键词： Bip tau GSK3β

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The effect of C-terminal fragment of JNK2 on the stability of p53 and cell proliferation

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Cell Research 2004年第5期14卷 434-438页

作者： zhi Min YIN1,*, jian SIMA1, Yi Fan WU1, jian ZHU1, Yong jianG2 1jiangsu province key laboratory of Biochemistry and Molecular Biology, College of Life science, Nanjing Normal university, Nanjing 210097, china 2department of pathophysiology and key Lab for Shock and Microcirculation of PLA, The First Military medical university, Guangzhou 510515, china jiangsu province key laboratory of Biochemistry and Molecular Biology College of Life Science Nanjing Normal University Nanjing 210097 China. Zhiminy_2000@***

The basal activity of JNK is low in normal growing cells and inactivated JNK targets p53 for ubiquitination. To elucidate if the C-terminal part of JNK is responsible for its binding to p53, the low background tet-off inducible NIH3T3 cell line was selected by luciferase reporter gene and a double stable C-JNK Aa (203-424) cell line was established. After withdrawing tetracycline, the C-JNK fragment expression was induced and cell growth was dramati- cally inhibited 24 h later. However, the expresion of p53 was found to be increased after the induction of C-JNK fragment, evaluated by transfecting p21waf-luciferase reporter genes. Our further studies showed that C-JNK fragment could form complex with p53 both in vivo and in vitro. Induction of C-JNK fragment in vivo can increase p53 stability by inhibiting p53 ubiquitination.

关键词： tet-off expression system c-Jun N-terminal kinase p53 cell proliferation.

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Phosphorylation-dependent regulation of APP by PP2A is involved in Aβ production

Phosphorylation-dependent regulation of APP by PP2A is invol...

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中国神经科学学会第九届全国学术会议暨第五次会员代表大会

作者： Xin Zhou~1,Gong-Ping LIU~1,jian-zhi wang~* 1 department of pathophysiology,key laboratory of neurological Disease of Education Ministry of china,tongji medical College,huazhong university of science and technology,wuhan 430030,china

＜正＞Objective In the amyloidogenic pathway,cleavage of APP by p-secretase generates an N-terminal soluble fragment（sAPP）and beta C-terminal fragment that is sequentially cleaved by y-secretase to produce the Aβpeptides. Threonine 668（T668）in the cytoplasmic domain of APP can be phosphorylated in vivo by a number of protein kinases,including GSK-3P,CDK5,CDC2 and JNK *** of these kinases are associated with neurotoxicity and implicated in neurodegenerative *** may play a key role in regulating the stability of APP,its interaction with intracellular partners and downstream signaling *** has been well recognized that an imbalanced regulation in protein kinases and protein phosphatases is the direct cause for the AD *** doubt that PP2A which considered being involved in the pathogenesis of AD can affect phosphorylation of APP at T668 to regulate Aβ*** N2a cells stable transfected with human APP（N2a-APP）were transiently transfected with GFP-PP2AsiRNA and Dsred-PP2A,Forty-eight hours after transfection,the protein level of phosphor-APP and total APP were determined by *** N2a-APP cells and the hippocampus of SD rats were also administrated with Okadaic acid（OA）or DES（c6-ceramide）by 24 *** Immunoblot was used to detect the level of phosphor-APP and *** Abeta level of cells and animals were detected by ELISA ***（1）Inhibition of PP2A by OA or siRNA can increase the phosphorylation of APP.（2）Activation of PP2A by DES or overexpression seems not affect the level of phosphor-APP.（3）The incretion of phosphor-APP by OA may not only owe to ***1 as an important phosphatases inhibited by OA may play a role in phosphorylation of APP and Abeta secretion.（4）The Aβlevel increased after injection on hippocampus of SD rats with 0.6 uM *** These results indicated that PP2A which considered to be involved in the pathogenesis of AD can affect phosphorylation of APP at T668 to regulate Aβgeneratio

关键词： APP Aβ PP2A T668

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Activation of glycogen synthase kinase-3 inhibits long term potentiation with synapse-associated impairments

Activation of glycogen synthase kinase-3 inhibits long term ...

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中国神经科学学会第四次会员代表大会暨第七届全国学术会议

作者： Ling-Qiang ZHU,Shao-Hui wang,Dan LIU,Yang-Yang YIN,Qing TIAN,Xiao-Chuan wang,Qun wang,Lian-Jun GUO,jian-Guo CHEN,jian-zhi wang department of pathophysiology,hubei Provincial key laboratory of neurological diseases,tongji medical College, huazhong university of science and technology,wuhan 430030 china

＜正＞Activation of glycogen synthase kinase-3（GSK-3） can cause memory deficits as seen in Alzheimer disease（AD）, the most common age-associated dementia,but the mechanism is not ***,we found that activation of GSK-3 by wortmannin or transient overexpression of wild type GSK-3β（wtGSK-3β） could suppress the induction of long term potentiation （LTP） in rat hippocampus,while simultaneous inhibition of GSK-3 by lithium or SB216763 or transient expression of a dominant negative GSK-3βmutant（dnGSK-3β） preserved the *** high frequency stimulation（HFS）,the presynaptic release of glutamate and the expression/clustering of synapsin I,a synaptic vesicle protein playing an important role in neurotransmitter release,decreased markedly upon upregulation of *** vitro studies further demonstrated that GSK-3 inhibited the expression of SynI independent of *** postsynaptic level,the expression of PSD93 and NR2A/B proteins decreased significantly when GSK-3 was *** LTP-associated synapse impairments including less presynaptic active zone,thinner postsynaptic density（PSD） and broader synaptic cleft were also prominent in the hippocampal slices after HFS with activation of *** synaptic impairments were attenuated when GSK-3 was simultaneously inhibited by LiCl or SB216763 or transient expression of *** conclude that upregulation of GSK-3 impairs the synaptic plasticity both functionally and structurally,which may underlie the GSK-3-involved memory deficits.

关键词： Gsk-3 synaptic plasticity

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