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NLRP3-dependent pyroptosis is required for HIV-1 gp120- induced neuropathology

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Cellular & Molecular Immunology 2020年第3期17卷 283-299页

作者： Xiaolong He Weijun Yang Zhijie Zeng Yi Wei Jie Gao Bao Zhang Li Li Liqun Liu Yu Wan Qing Zeng Zelong Gong Liting Liu Hanyun Zhang Yubin Li Shaojie Yang Tongtong Hu Lixian Wu Eliezer Masliah Shenghe Huang Hong Cao Department of Microbiology Guangdong Provincial Key Laboratory of Tropical Disease ResearchSchool of Public HealthSouthern Medical UniversityGuangzhou 510515China Kunming Key Laboratory of Children Infection and Immunity Yunnan Institute of PediatricsKunming Children’s HospitalKunmingYunnan 650228China Department of Pediatrics The Second Xiangya HospitalCentral South UniversityChangsha 410011China Department of Medical Microbiology and Immunology Dali UniversityDali 671000China Division of Neurosciences National Institute on AgingNational Institutes of HealthBethesdaMD 20892USA Departments of Neuroscience and Pathology University of CaliforniaSan DiegoLa JollaCA 92093USA Saban Research Institute Children’s Hospital Los AngelesUniversity of Southern CaliforniaLos AngelesCA 90027USA

The human immunodeficiency virus-1(HIV-1)envelope protein gp120 is the major contributor to the pathogenesis of HIVassociated neurocognitive disorder(HAND).Neuroinflammation plays a pivotal role in gp120-induced neuropathology,but how gp120 triggers neuroinflammatory processes and subsequent neuronal death remains unknown.Here,we provide evidence that NLRP3 is required for gp120-induced neuroinflammation and neuropathy.Our results showed that gp120-induced NLRP3-dependent pyroptosis and IL-1βproduction in microglia.Inhibition of microglial NLRP3 inflammasome activation alleviated gp120-mediated neuroinflammatory factor release and neuronal injury.Importantly,we showed that chronic administration of MCC950,a novel selective NLRP3 inhibitor,to gp120 transgenic mice not only attenuated neuroinflammation and neuronal death but also promoted neuronal regeneration and restored the impaired neurocognitive function.In conclusion,our data revealed that the NLRP3 inflammasome is important for gp120-induced neuroinflammation and neuropathology and suggest that NLRP3 is a potential novel target for the treatment of HAND.

关键词： NLRP3 inflammasome HIV-1 gp120 HIV-associated neurocognitive disorder Neuroinflammation neuropathology

Transplantation of bone marrow mesenchymal stem cells improves cognitive deficits and alleviates neuropathology in animal models of Alzheimer’s disease: a meta-analytic review on potential mechanisms

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Translational Neurodegeneration 2020年第2期9卷 214-233页

作者： Chuan Qin Yalan Lu Kewei Wang Lin Bai Guiying Shi Yiying Huang Yongning Li Institute of Laboratory Animal Sciences Chinese Academy of Medical Sciences&Comparative Medical CenterPeking Union Medical CollegeBeijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases5 Panjiayuan Nanli StBeijing100021China Department of International Medical Service&Department of Neurosurgery Peking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeShuaifuyuan 1Dong Cheng DistrictBeijing100730China

Background Alzheimer’s disease is a neurodegenerative disorder.Therapeutically,a transplantation of bone marrow mesenchymal stem cells(BMMSCs)can play a beneficial role in animal models of Alzheimer’s disease.However,the relevant mechanism remains to be fully elucidated.Main body Subsequent to the transplantation of BMMSCs,memory loss and cognitive impairment were significantly improved in animal models with Alzheimer’s disease(AD).Potential mechanisms involved neurogenesis,apoptosis,angiogenesis,inflammation,immunomodulation,etc.The above mechanisms might play different roles at certain stages.It was revealed that the transplantation of BMMSCs could alter some gene levels.Moreover,the differential expression of representative genes was responsible for neuropathological phenotypes in Alzheimer’s disease,which could be used to construct gene-specific patterns.Conclusions Multiple signal pathways involve therapeutic mechanisms by which the transplantation of BMMSCs improves cognitive and behavioral deficits in AD models.Gene expression profile can be utilized to establish statistical regression model for the evaluation of therapeutic effect.The transplantation of autologous BMMSCs maybe a prospective therapy for patients with Alzheimer’s disease.

关键词： Alzheimer's disease Bone marrow mesenchymal stem cells Meta-analysis Amyloid P peptide Memory loss Cognitive deficits Animal model neuropathology

Security breach:peripheral nerves provide unrestricted access for toxin delivery into the central nervous system

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中国神经再生研究：英文版 2023年第1期18卷 64-67页

作者： Igor Lupinski Allison SLiang Randall D.McKinnon Department of Neurosurgery and Member The Cancer Institute of New JerseyRutgers-Robert Wood Johnson Medical SchoolPiscatawayNJUSA

We explore the hypothesis that a potential explanation for the initiation of motor neuron disease is an unappreciated vulnerability in central nervous system defense,the direct delivery of neurotoxins into motor neurons via peripheral nerve retrograde transport.This further suggests a mechanism for focal initiation of neuro-degenerative diseases in general,with subsequent spread by network degeneration as suggested by the Frost-Diamond hypothesis.We propose this vulnerability may be a byproduct of vertebrate evolution in a benign aquatic environment,where external surfaces were not exposed to concentrated neurotoxins.

关键词： amyotrophic lateral sclerosis bioaccumulation neurodegeneration neuropathology neurotoxins peripheral nerves retrograde transport retrotoxicity suicide transport

Steroid receptor coactivator-1:The central intermediator linking multiple signals and functions in the brain and spinal cord

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Genes & Diseases 2022年第5期9卷 1281-1289页

作者： Zhaoyou Meng Xiaoya Wang Dongmei Zhang Zhen Lan Xiaoxia Cai Chen Bian Jiqiang Zhang Department of Neurobiology Army Medical UniversityChongqing 400038PR China Department of Neurosurgery Nanchong Central Hospitalthe Second Clinical Medical CollegeNorth Sichuan Medical CollegeNanchongSichuan 637000PR China Department of Dermatology Southwest HospitalArmy Medical UniversityChongqing 400038PR China School of Life Sciences Southwest UniversityChongqing 400715PR China School of Psychology Amy Medical UniversityChongqing 400038PR China

The effects of steroid hormones are believed to be mediated by their nuclear receptors(NRs).The p160 coactivator family,including steroid receptor coactivator-1(SRC-1),2 and 3,has been shown to physically interact with NRs to enhance their transactivational activities.Among which SRC-1 has been predominantly localized in the central nervous system including brain and spinal cord.It is not only localized in neurons but also detectable in neuroglial cells(mainly localized in the nuclei but also detectable in the extra-nuclear components).Although the expression of SRC-1 is regulated by many steroids,it is also regulated by some non-steroidal factors such as injury,sound and light.Functionally,SRC-1 has been implied in normal function such as development and ageing,learning and memory,central regulation on reproductive behaviors,motor and food intake.Pathologically,SRC-1 may play a role in the regulation of neuropsychiatric disorders(including stress,depression,anxiety,and autism spectrum disorder),metabolite homeostasis and obesity as well as tumorigenesis.Under most conditions,the related mechanisms are far from elucidation;although it may regulate spatial memory through Rictor/mTORC2-actin polymerization related synaptic plasticity.Several inhibitors and stimulator of SRC-1 have shown anti-cancer potentials,but whether these small molecules could be used to modulate ageing and central disorder related neuropathology remain unclear.Therefore,to elucidate when and how SRC-1 is turned on and off under different stimuli is very interesting and great challenge for neuroscientists.

关键词： Cognition neuropathology Neuropsychiatry Steroid Steroid receptor coactivator-1 Synaptic plasticity

Exosomes as mediators of neuron-glia communication in neuroinflammation

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Neural Regeneration Research 2020年第5期15卷 796-801页

作者： María Pascual Francesc Ibánez Consuelo Guerri Department of Molecular and Cellular Pathology of Alcohol Príncipe Felipe Research CenterValenciaSpain Department of Physiology School of Medicine and DentistryUniversity of ValenciaValenciaSpain

In recent years,a type of extracellular vesicles named exosomes has emerged that play an important role in intercellular communication under physiological and pathological conditions.These nanovesicles (30–150 nm) contain proteins,RNAs and lipids,and their internalization by bystander cells could alter their normal functions.This review focuses on recent knowledge about exosomes as messengers of neuron-glia communication and their participation in the physiological and pathological functions in the central nervous system.Special emphasis is placed on the role of exosomes under toxic or pathological stimuli within the brain,in which the glial exosomes containing inflammatory molecules are able to communicate with neurons and contribute to the pathogenesis of neuroinflammation and neurodegenerative disorders.Given the small size and characteristics of exosomes,they can cross the blood-brain barrier and be used as biomarkers and diagnosis for brain disorders and neuropathologies.Finally,although the application potential of exosome is still limited,current studies indicate that exosomes represent a promising strategy to gain pathogenic information to identify therapeutically targets and biomarkers for neurological disorders and neuroinflammation.

关键词： biomarkers exosomes glial cells neuroinflammation neuron-glia commuication neurons neuropathology therapy

Amelioration of Alzheimer's disease pathology and cognitive deficits by immunomodulatory agents in animal models of Alzheimer's disease

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Neural Regeneration Research 2019年第7期14卷 1158-1176页

作者： Bridget Martinez Philip V.Peplow Department of Molecular & Cellular Biology University of California Department of Medicine St.Georges University School of Medicine Department of Physics and Engineering Los Alamos National Laboratory Department of Anatomy University of Otago

The most common age-related neurodegenerative disease is Alzheimer's disease(AD) characterized by aggregated amyloid-β(Aβ) peptides in extracellular plaques and aggregated hyperphosphorylated tau protein in intraneuronal neurofibrillary tangles,together with loss of cholinergic neurons,synaptic alterations,and chronic inflammation within the brain.These lead to progressive impairment of cognitive function.There is evidence of innate immune activation in AD with microgliosis.Classically-activated microglia(M1 state) secrete inflammatory and neurotoxic mediators,and peripheral immune cells are recruited to inflammation sites in the brain.The few drugs approved by the US FDA for the treatment of AD improve symptoms but do not change the course of disease progression and may cause some undesirable effects.Translation of active and passive immunotherapy targeting Aβ in AD animal model trials had limited success in clinical trials.Treatment with immunomodulatory/anti-inflammatory agents early in the disease process,while not preventive,is able to inhibit the inflammatory consequences of both Aβ and tau aggregation.The studies described in this review have identified several agents with immunomodulatory properties that alleviated AD pathology and cognitive impairment in animal models of AD.The majority of the animal studies reviewed had used transgenic models of early-onset AD.More effort needs to be given to creat models of late-onset AD.The effects of a combinational therapy involving two or more of the tested pharmaceutical agents,or one of these agents given in conjunction with one of the cell-based therapies,in an aged animal model of AD would warrant investigation.

关键词： Alzheimer’s disease neuropathology cognitive deficits behavioral deficits immunomodulatory agents animal models amyloid deposits gliosis

Expert Consensus on Clinical Diagnostic Criteria for Fatal Familial Insomnia

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Chinese Medical Journal 2018年第13期131卷 1613-1617页

作者： Li-Yong Wu Shu-Qin Zhan Zhao-Yang Huang Bin Zhang Tao Wang Chun-Feng Liu Hui Lu Xiao-Ping Dong Zhi-Ying Wu Jie-Wen Zhang Ji-Hui Zhang Zhong-Xin Zhao Fang Han Yah Huang Jun Lu Serge Gauthier Jian-Ping Jia Yu-Ping Wang Department of Neurology Xuan Wu Hospital Capital Medical University Belling 100053 China Department of Psychiatry Nanfang Hospital Southern Medical University Guangzhou Guangdong 510515 China Department of Neurology Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei 430022 China Department of Neurorogy Second Affiliated Hospital of Soochow University Suzhou Jiangsu 215004 China State Key Laboratory for Infectious Disease Prevention and Control National Institute for Viral Disease Control and Prevention Chinese Center for Disease Control and Prevention Beijing 100050 China Department of Neurology and Research Center of Neurology Second Affiliated Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310009 China Department of Neurology Henan Provincial People's Hospital Zhengzhou Henan 450003 China Department of Psychiatry Faculty of Medicine The Chinese University of Hong Kong Shatin NT Hong Kong SAR 000000 China Department of Neurology Changzheng Hospital The Second Military Medical University Shanghai 200003 China Department of Respiratory Medicine Peking University People's Hospital Beijing 100044 China Department of Neurology Peking Union Medical College Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100730 China Department of Neurology Program in Neuroscience and Division of Sleep Medicine Harvard Medical School and Beth Israel Deaconess Medical Center Boston 02215 MA USA McGill Centre for Studies in Aging Alzheimer's Disease Research Unit Montreal H4H 1R3 Canada

INTRODUCTION Fatal familial insomnia （FFI） is a serious and rare prion disease, which was first reported by Lugaresi et al. in 1986.Early diagnosis of FFI might be important for early and sufficient counseling of patients and their relatives, also concerning the risk of inheritance, and potentially also for treatment studies. However, the diagnosis of FFI might be difficult because of the heterogeneity of clinical features, low sensitivity of diagnostic tests, and absence of family history. The aim of the present study was to develop a clinical scheme and diagnostic criteria for FFI based on our research and expert consensus.

关键词： HUMAN PRION DISEASES CREUTZFELDT-JAKOB-DISEASE PROTEIN neuropathology DEGENERATION FEATURES DISORDERS THALAMUS MUTATION ONSET

Schizophrenia-associated MicroRNA–Gene Interactions in the Dorsolateral Prefrontal Cortex

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Genomics, Proteomics & Bioinformatics 2019年第6期17卷 623-634页

作者： Danielle M.Santarelli Adam P.Carroll Heath M.Cairns Paul A.Tooney Murray J.Cairns School of Biomedical Sciences and Pharmacy The University of NewcastleCallaghanNSW 2308Australia Centre for Brain and Mental Health Research Hunter Medical Research InstituteNewcastleNSW 2305Australia

Schizophrenia-associated anomalies in gene expression in postmortem brain can be attributed to a combination of genetic and environmental influences. Given the small effect size of common variants, it is likely that we may only see the combined impact of some of these at the pathway level in small postmortem studies. At the gene level, however, there may be more impact from common environmental exposures mediated by influential epigenomic modifiers, such as microRNA(miRNA). We hypothesise that dysregulation of miRNAs and their alteration of gene expression have significant implications in the pathophysiology of schizophrenia. In this study, we integrate changes in cortical gene and miRNA expression to identify regulatory interactions and networks associated with the disorder. Gene expression analysis in post-mortem prefrontal dorsolateral cortex(BA 46)(n = 74 matched pairs of schizophrenia, schizoaffective, and control samples)was integrated with miRNA expression in the same cohort to identify gene–miRNA regulatory networks. A significant gene–miRNA interaction network was identified, including miR-92 a, miR-495,and miR-134, which converged with differentially expressed genes in pathways involved in neurodevelopment and oligodendrocyte function. The capacity for miRNA to directly regulate gene expression through respective binding sites in BCL11 A, PLP1, and SYT11 was also confirmed to support the biological relevance of this integrated network model. The observations in this study support the hypothesis that mi RNA dysregulation is an important factor in the complex pathophysiology of schizophrenia.

关键词： Schizophrenia MicroRNA Dorsolateral prefrontal cortex Network neuropathology

Gut dysbiosis aggravates cognitive deficits,amyloid pathology and lipid metabolism dysregulation in a transgenic mouse model of Alzheimer's disease

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Journal of Pharmaceutical Analysis 2023年第12期13卷 1526-1547页

作者： Chang Qu Qing-Qing Xu Wen Yang Mei Zhong Qiuju Yuan Yan-Fang Xian Zhi-Xiu Lin School of Chinese Medicine Faculty of MedicineThe Chinese University of Hong KongHong KongChina College of Forestry and Landscape Architecture South China Agricultural UniversityGuangzhou510640China Centre for Regenerative Medicine and Health Hong Kong Institute of Science&InnovationChinese Academy of SciencesHong Kong Science ParkShatinN.T.Hong KongChina Hong Kong Institute of Integrative Medicine The Chinese University of Hong KongHong KongChina

Gut dysbiosis,a well-known risk factor to triggers the progression of Alzheimer's disease(AD),is strongly associated with metabolic disturbance.Trimethylamine N-oxide(TMAO),produced in the dietary choline metabolism,has been found to accelerate neurodegeneration in AD pathology.In this study,the cognitive function and gut microbiota of TgCRND8(Tg)mice of different ages were evaluated by Morris water maze task(MWMT)and 16S rRNA sequencing,respectively.Young pseudo germ-free(PGF)Tg mice that received faecal microbiota transplants from aged Tg mice and wild-type(WT)mice were selected to determine the role of the gut microbiota in the process of neuropathology.Excessive choline treatment for Tg mice was used to investigate the role of abnormal choline metabolism on the cognitive functions.Our results showed that gut dysbiosis,neuroinflammation response,Ab deposition,tau hyperphosphorylation,TMAO overproduction and cyclin-dependent kinase 5(CDK5)/transcription 3(STAT3)activation occurred in Tg mice age-dependently.Disordered microbiota of aged Tg mice accelerated AD pathology in young Tg mice,with the activation of CDK5/STAT3 signaling in the brains.On the contrary,faecal microbiota transplantation from WT mice alleviated the cognitive deficits,attenuated neuroinflammation,Ab deposition,tau hyperphosphorylation,TMAO overproduction and suppressed CDK5/STAT3 pathway activation in Tg mice.Moreover,excessive choline treatment was also shown to aggravate the cognitive deficits,Ab deposition,neuroinflammation and CDK5/STAT3 pathway activation.These findings provide a novel insight into the interaction between gut dysbiosis and AD progression,clarifying the important roles of gut microbiota-derived substances such as TMAO in AD neuropathology.

关键词： Alzheimer's disease Gut dysbiosis neuropathology TgCRND8 mice