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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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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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Illuminating Neural Circuits in Alzheimer’s Disease

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Neuroscience Bulletin 2021年第8期37卷 1203-1217页

作者： Yang Ying jian-zhi wang Department of Pathophysiology School of Basic MedicineMinistry of Education Key Laboratory for Neurological DisordersHubei Key Laboratory for Neurological DisordersTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China

Alzheimer’s disease(AD)is the most common neurodegenerative disorder and there is currently no *** circuit dysfunction is the fundamental mechanism underlying the learning and memory deficits in patients with ***,it is important to understand the structural features and mechanisms underlying the deregulated circuits during AD progression,by which new tools for intervention can be ***,we briefly summarize the most recently established cutting-edge experimental approaches and key techniques that enable neural circuit tracing and manipulation of their *** also discuss the advantages and limitations of these ***,we review the applications of these techniques in the discovery of circuit mechanisms underlyingβ-amyloid and tau pathologies during AD progression,and as well as the strategies for targeted AD treatments.

关键词： Neural circuit Alzheimer’s disease Single cell RNA sequencing Neural circuit tracing Optogenetics Chemogenetics

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Tau hyperphosphorylation induces apoptotic escape and triggers neurodegeneration in Alzheimer's disease

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Neuroscience Bulletin 2014年第2期30卷 359-366页

作者： jian-zhi wang zhi-Hao wang Qing Tian Department of Pathology and Pathophysiology Key Laboratory of Ministry of Education of China for Neurological DisordersTongji Medical College Huazhong University of Science and Technology

Since abnormal post-translational modifications or gene mutations of tau have been detected in over twenty neurodegenerative disorders, tau has attracted widespread interest as a target protein. Among its various post-translational modifications, phosphorylation is the most extensively studied. It is recognized that tau hyperphosphorylation is the root cause of neurodegeneration in Alzheimer＇s disease （AD）; however, it is not clear how it causes neurodegeneration. Based on the findings that tau hyperphosphorylation leads to the escape of neurons from acute apoptosis and simultaneously impairs the function of neurons, we have proposed that the nature of AD neurodegeneration is the consequence of aborted apoptosis induced by tau phosphorylation. Therefore, proper manipulation of tau hyperphosphorylation could be promising for arresting AD neurodegeneration. In this review, the neuroprotective and neurodegenerative effects of tau hyperphosphorylation and our thoughts regarding their relationship are presented.

关键词： Alzheimer's disease microtubule-associated protein tau hyperphosphorylaUon apoptosis neurodegeneration

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A Parallel Genetic Algorithm Based on Spark for Pairwise Test Suite Generation

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Journal of Computer Science & Technology 2016年第2期31卷 417-427页

作者： Rong-zhi Qi zhi-jian wang Shui-Yan Li College of Computer and Information Hohai University Nanjing 211106 China CoUege of Science Hohai University Nanjing 211106 China

Pairwise testing is an effective test generation technique that requires all pairs of parameter values to be by at least one test case. It has been proven that generating minimum test suite is an NP-complete problem covered Genetic algorithms have been used for pairwise test suite generation by researchers. However, it is always a time-consuming process, which leads to significant limitations and obstacles for practical use of genetic algorithms towards large-scale test problems. Parallelism will be an effective way to not only enhance the computation performance but also improve the quality of the solutions. In this paper, we use Spark, a fast and general parallel computing platform, to parallelize the genetic algorithm to tackle the problem. We propose a two-phase parallelization algorithm including fitness evaluation parallelization and genetic operation parallelization. Experimental results show that our algorithm outperforms the sequential genetic algorithm and competes with other approaches in both test suite size and computational performance. As a result, our algorithm is a promising improvement of the genetic algorithm for pairwise test suite generation.

关键词： pairwise testing parallel genetic algorithm Spark test generation

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Alzheimer's disease: from molecule to clinic

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Neuroscience Bulletin 2014年第2期30卷 169-171页

作者： jian-zhi wang Department of Pathophysiology Key Laboratory of Neurological Diseases of The Ministry of Education Tongji Medical College Huazhong University of Science and Technology

AIzheimer＇s disease （AD） is the most common neurodegenerative disorder and is characterized pathologically by the progressive intracellular accumulation of neurofibrillary tangles and extracellular deposition of plaques in the brain. Since hyperphosphorylated tau and ^-amyloid （A/3） are respectively the major components of the tangles and the plaques, recent studies have mainly focused on the alterations associated with these two molecules. Clinically, AD features memory deterioration. More than 6 million patients in China alone are suffering from this devastating disease, and this figure is increasing with the acceleration of population ageing. Although many specific aspects of AD have been documented, the disease is hard to diagnose in the early stage and the efficacy of current treatments is very limited. Therefore, AD is attracting worldwide attention.

关键词： from molecule to clinic Alzheimer’s disease AD

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多肽靶向嵌合体通过促进tau蛋白特异性去磷酸化治疗阿尔茨海默病和其他tau蛋白病

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Science Bulletin 2024年第8期69卷 1137-1152页

作者：苏静芬肖越魏林郁雷慧杨孙飞王围霞尹君熊瑞李师宏张配周颖王小川郑杰王建枝 Department of Pathophysiology School of Basic MedicineKey Laboratory of Education Ministry of China/Hubei Province for Neurological DisordersTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China School of Artificial Intelligence and Automation Huazhong University of Science and TechnologyWuhan 430030China Sino-UK Joint Laboratory of Brain Function and Injury of Henan Province Department of Physiology and PathophysiologySchool of Basic Medical SciencesXinxiang Medical UniversityXinxiang 453003China Department of Pathophysiology School of Basic Medical SciencesWuhan UniversityWuhan 430030China Department of Anesthesiology The First Affiliated Hospital of Gannan Medical UniversityGanzhou 341000China The Core Facility and Technical Support Wuhan Institute of VirologyChinese Academy of SciencesWuhan 430030China Research Center for Medicine and Structural Biology Wuhan UniversityWuhan 430030China Neuroscience Research Institute and Department of Neurobiology School of Basic Medical SciencesPeking UniversityKey Laboratory for NeuroscienceMinistry of Education/National Health CommissionBeijing 100083China Co-innovation Center of Neuroregeneration Nantong UniversityNantong 226000China

Abnormal hyperphosphorylation and accumulation of tau protein play a pivotal role in neurodegeneration in Alzheimer’s disease(AD)and many other *** elimination of hyperphosphorylated tau is promising for the therapy of these *** have conceptualized a strategy,named dephosphorylation-targeting chimeras(DEPTACs),for specifically hijacking phosphatases to tau to debilitate its ***,we conducted the step-by-step optimization of each constituent motif to generate DEPTACs with reasonable effectiveness in facilitating the dephosphorylation and subsequent clearance of pathological ***,for one of the selected chimeras,D16,we demonstrated its significant efficiency in rescuing the neurodegeneration caused by neurotoxic K18-tau seeds in ***,intravenous administration of D16 also alleviated tau pathologies in the brain and improved memory deficits in AD *** results suggested DEPTACs as targeted modulators of tau phosphorylation,which hold therapeutic potential for AD and other tauopathies.

关键词： tau Dephosphorylation-targeting chimeras Therapeutic potential Tauopathy

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The dual roles of cytokines in Alzheimer’s disease:update on interleukins, TNF-α,TGF-β and IFN-γ

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Translational Neurodegeneration 2016年第1期5卷 52-66页

作者： Cong Zheng Xin-Wen Zhou jian-zhi wang Department of Pathophysiology School of Basic Medicine and the Collaborative Innovation Center for Brain ScienceKey Laboratory of Ministry of Education of China for Neurological DisordersTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China Co-innovation Center of Neuroregeneration Nantong 226000China

Alzheimer’s disease(AD)is one of the most common neurodegenerative disorders in the *** the mechanisms underlying AD neurodegeneration are not fully understood,it is well recognized that inflammation plays a crucial role in the initiation and/or deterioration of AD *** evidence suggests that different cytokines,including interleukins,TNF-α,TGF-βand IFN-γ,are actively participated in AD pathogenesis and may serve as diagnostic or therapeutic targets for AD ***,we review the progress in understanding the important role that these cytokines or neuroinflammation has played in AD etiology and pathogenesis.

关键词： Alzheimer’s disease Cytokines Interleukins TNF-α TGF-β IFN-γ

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PREVALENCE OF IMPAIRED GLUCOSE REGULATION IN THE POPULATION OF TIANJIN

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Chinese Medical Sciences Journal 2008年第4期23卷 249-252页

作者： Xin-yue zhi jian-hua wang Department of Epidemiology School of Public Health Tianjin Medical University Tianjin 300070

Objective To investigate the prevalence of impaired glucose regulation （IGR） in the population of Tianjin. Methods A cross-sectional study was conducted in Tianjin from June to September in 2005. The multi-phasic stratified cluster sampling method was adopted. Totally, 21454 people were selected as survey sample. Information on risk factors was collected through face-to-face questionnaire interview. Fasting capillary whole blood glucose level and other clinical indexes were tested. Results The prevalence of impaired fasting glucose （IFG） in the population was 5.61% （5.32% in male, 5.89% in female）. The prevalence of impaired glucose tolerance （IGT） was 2.91% （2.59% in male, 3.20% in female） in whole population, and the prevalence of female was significantly higher than that of male （P = 0.04）. The prevalences of IFG and IGT increased with the increasing of age. And the prevalences were also influenced by the profession, educational level, and income level. Conclusion The prevalences oflGT and IFG in Tianjin are similar to those in the other big cities of China.

关键词： impaired glucose regulation population prevalence

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Folate/Vitamin B Alleviates Hyperhomocysteinemia-Induced Alzheimer-Like Pathologies in Rat Retina

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Neuroscience Bulletin 2019年第2期35卷 325-335页

作者： Jing Guo Shaozhou Ni Qihang Li jian-zhi wang Ying Yang Department of Pathophysiology School of Basic Medicine and Collaborative Innovation Center for Brain Science Key Laboratory for Neurological Disorders of the Ministry of Education of China Tongji Medical College Huazhong University of Science and Technology Emergency Department Zhongnan Hospital of Wuhan University School of Optometry and Ophthalmology and Eye Hospital Wenzhou Medical College Co-innovation Center of Neuroregeneration Nantong University

Hyperhomocysteinemia(Hhcy) is an independent risk factor for Alzheimer's disease(AD). Visual dysfunction is commonly found and is positively correlated with the severity of cognitive defects in AD patients. Our previous study demonstrated that Hhcy induces memory deficits with AD-like tau and amyloid-b(Ab) pathologies in the hippocampus, and supplementation with folate and vitamin B12(FB) prevents the Hhcy-induced AD-like pathologies in the hippocampus. Here, we investigated whether Hhcy also induces AD-like pathologies in the retina and the effects of FB. An Hhcy rat model was produced by vena caudalis injection of homocysteine for14 days, and the effects of FB were assessed by simultaneous supplementation with FB in drinking water. We found that Hhcy induced vessel damage with Ab and taupathologies in the retina, while simultaneous supplementation with FB remarkably attenuated the Hhcy-induced tau hyperphosphorylation at multiple AD-related sites and Ab accumulation in the retina. The mechanisms involved downregulation of amyloid precursor protein(APP), presenilin-1, beta-site APP-cleaving enzyme 1, and protein phosphatase-2 A. Our data suggest that the retina may serve as a window for evaluating the effects of FB on hyperhomocysteinemia-induced Alzheimer-like pathologies.

关键词： Hyperhomocysteinemia Alzheimer’s disease Retina Folate Vitamin B12

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