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Sphingosine-1-phosphate,a novel TREM2 ligand,promotes microglial phagocytosis to protect against ischemic brain injury

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Acta Pharmaceutica Sinica B 2022年第4期12卷 1885-1898页

作者： Tengfei Xue Juan Ji Yuqin Sun Xinxin Huang Zhenyu Cai Jin Yang Wei Guo Ruobing Guo Hong Cheng Xiulan Sun Department of Pharmacology Neuroprotective Drug Discovery Key LaboratoryJiangsu Key Laboratory of NeurodegenerationNanjing Medical UniversityNanjing 211166China Nanjing University of Chinese Medicine the Affiliated Hospital of Nanjing University of Chinese MedicineNanjing 210004China The First Affiliated Hospital of Nanjing Medical University Nanjing 210029China

The mechanism of sphingosine-1-phosphate(S1P)-mediated phagocytosis remains unknown.Here,we found that S1P or FTY720(an analog of S1P)promoted microglial phagocytosis in stroke independent of S1PRs.First,we used computer simulation of molecular docking to predict that S1P might be a ligand for triggering receptor expressed on myeloid cells 2(TREM2).Next,microscale thermophoresis(MST),surface plasmon resonance(SPR)and liquid chromatography–tandem mass spectrometry(LC–MS/MS)were performed to reveal that S1P was a novel TREM2 ligand.Then,we confirmed the pro-phagocytosis of S1P targeting in Trem2-Dap12 transfected CHO cells and TREM2 knockdown microglia.Point mutation analysis showed that D104 was the critical binding residue.Trem2^(−/−)mice were used to demonstrate the role of S1P-induced phagocytosis targeting on TREM2 in protecting against ischemic brain injury.Finally,further studies revealed that apolipoprotein E(apoe)loaded with S1P was released by microglia and bound to apoptotic neurons via LDL receptor related protein 1B(LRP1B)and thereby induced microglia to phagocytose apoptotic neurons.Overall,the present work reveals for the first time that S1P acts as a novel endogenous ligand of TREM2 to effectively promote microglial phagocytosis.Our findings provide a new lead compound for developing immunomodulator targeting on TREM2.

关键词： S1P TREM2 Microglia Phagocytosis Stroke apoe LRP1B Apoptotic neurons

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Dogs lacking Apolipoprotein E show advanced atherosclerosis leading to apparent clinical complications

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Science China(Life Sciences) 2022年第7期65卷 1342-1356页

作者： Hui Zhao Jianping Zhao Di Wu Zhaolin Sun Yang Hua Min Zheng Yumei Liu Qi Yang Xiahe Huang Yuan Li Yueshan Piao Yingchun Wang Sin Man Lam Huijuan Xu Guanghou Shui Yongjun Wang Haifeng Yao Liangxue Lai Zhuo Du Jidong Mi Enqi Liu Xunming Ji Yong Q.Zhang Key Laboratory of Molecular Developmental Biology and CAS Center for Excellence in Brain Science and Intelligence TechnologyInstitute ofGenetics and Developmental BiologyChinese Academy of SciencesBeijing 100101China Guangzhou Institutes of Biomedicine and Health Chinese Academy of SciencesGuangzhou 510530China Beijing Sinogene Biotechnology Co.Ltd Beijing 102200China Xuanwu Hospital Capital Medical UniversityBeijing 100053China TianTan Hospital Capital Medical UniversityBeijing 100070China Beijing Petsguard Animal Hospital Beijing 100192China Laboratory Animal Center Xi’an Jiaotong University Health Science CenterXi’an 710049China

Atherosclerotic cardiovascular disease resulting from dysregulated lipid metabolism is the leading cause of morbidity and mortality worldwide.Apolipoprotein E(apoe)plays a critical role in cholesterol metabolism.Knockouts in lipid-metabolizing proteins including apoe in multiple model organisms such as mice and rats exhibiting elevated levels of cholesterol have been widely used for dissecting the pathology of atherosclerosis,but few of these animal models exhibit advanced atherosclerotic plaques leading to ischemia-induced clinical symptoms,limiting their use for translational studies.Here we report hypercholesterolemia and severe atherosclerosis characterized by stenosis and occlusion of arteries,together with clinical manifestations of stroke and gangrene,in apoe knockout dogs generated by CRISPR/Cas9 and cloned by somatic cell nuclear transfer technologies.Importantly,the hypercholesterolemia and atherosclerotic complications in F0 mutants are recapitulated in their offspring.As the apoe-associated atherosclerosis and clinical manifestations in mutant dogs are more similar to that in human patients compared with those in other animal models,these mutant dogs will be invaluable in developing and evaluating new therapies,including endovascular procedures,against atherosclerosis and related disorders.

关键词： apoe atherosclerosis hypercholesterolemia gangrene stroke

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The COVID-19 pandemic and Alzheimer’s disease: mutual risks and mechanisms

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Translational Neurodegeneration 2022年第1期11卷 343-360页

作者： Feng Chen Yanting Chen Yongxiang Wang Qiongwei Ke Lili Cui Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases Department of NeurologyAffiliated Hospital of Guangdong Medical Univer-sityZhanjiangChina Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences&Yunnan Province Kunming Institute of Zoology Chinese Academy of Sciences KunmingYunnanChina.

Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2), is a life-threatening disease, especially in elderly individuals and those with comorbidities. The predominant clinical manifestation of COVID-19 is respiratory dysfunction, while neurological presentations are increasingly being recognized. SARS-CoV-2 invades host cells primarily via attachment of the spike protein to the angiotensin-converting enzyme 2 (ACE2) receptor expressed on cell membranes. Patients with Alzheimer’s disease (AD) are more susceptible to SARS-CoV-2 infection and prone to severe clinical outcomes. Recent studies have revealed some common risk fac-tors for AD and COVID-19. An understanding of the association between COVID-19 and AD and the potential related mechanisms may lead to the development of novel approaches to treating both diseases. In the present review, we first summarize the mechanisms by which SARS-CoV-2 invades the central nervous system (CNS) and then discuss the associations and potential shared key factors between COVID-19 and AD, with a focus on the ACE2 receptor, apolipo-protein E (apoe) genotype, age, and neuroinflammation.

关键词： SARS-CoV-2 COVID-19 Alzheimer’s disease ACE2 apoe Age Neuroinflammation

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Effects of long-term,low-dose sex hormone replacement therapy on hippocampus and cognition of postmenopausal women of different apoe genotypes

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Acta Pharmacologica Sinica 2007年第8期28卷 1129-1135页

作者： Yun YUE~1 Ling HU~2 Qin-jie TIAN~2 Jing-mei JIANG~ 1 Yi-long DONG~1 Zheng-yu JIN~2 Yu-hang CHENG~3 Xia HONG~2 Qin-sheng GE~2 Ping-ping ZUO~(1,4) ~1School of Basic Medicine,Peking Union Medical College and Institute of Basic Medical Seience,Chinese Academy of Medical Sciences,Beijing 100005,China ~2Peking Union Medical College Hospital,Beijing 100730,China ~3Beijing Anding Hospital,Beijing 100088,China School of Basic Medicine Peking Union Medical College and Institute of Basic Medical Science Chinese Academy of Medical Sciences Beijing China Peking Union Medical College Hospital Beijing China Beijing Anding Hospital Beijing China

Aim:To study the effects of long-term,low-dose sex hormone replacement therapy(HRT)on the volume and biochemical changes of the hippocampus in postmeno-pausal women carrying apolipoprotein E(apoe)gene ε3 or ε4.Methods:Eighty-three postmenopausal women who had used a low dose of HRT for over 4 yearswere selected as the HRT group,and 99 postmenopausal women with matchedage and education were enrolled as the control group.apoe alleles were analyzedby PCR.Magnetic resonance imaging was performed to determine the volume ofthe brain hippocampus.Proton magnetic resonance spectroscopy was used todetect the biochemical changes in the anterior cingulate cortex and hippocampusin apoe ε4 and ε3 carriers.Six common cognitive tests were used to make anoverall evaluation of cognitive function.Results:Analysis with the apoe ε4carriers showed that the volume of the hippocampus of the control group weresignificantly lower than those of the HRT group.The biochemical analysis showedthat there was an increase of N-acetylaspartate(NAA)/total creatine(tCr)and adecrease of myoinositol(mI)/tCr in the hippocampus of apoe ε4 carriers in theHRT group,compared with the control group.For the apoe ε3 carriers,the leastsquares means(LSMEAN)of the HRT group was higher than that of the controlgroup.Conclusion:This study showed that long-term,low dose HRT might bebeneficial for reducing the risk of AD development in vulnerable postmenopausalwomen.Meanwhile,HRT could increase the LSMEAN of apoe ε3 carriers.

关键词： hormone replacement therapy apoe Alzheimer’s disease magnetic resonance imaging

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载脂蛋白E通过激活ERK/MMP9信号通路促进子宫内膜癌细胞的迁移

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南方医科大学学报 2023年第2期43卷 232-241页

作者：吴超英程文俊南京医科大学常州医学中心常州市妇幼保健院妇科江苏常州213000 南京医科大学第一附属医院妇科江苏南京210029

目的研究载脂蛋白E(apoe)在子宫内膜癌转移中的具体作用及分子调控机制。方法子宫内膜癌HEC-1B细胞常规培养,空白对照组siRNA以及apoe靶向的siRNA转染子宫内膜癌HEC-1B细胞,以及采用空载质粒和apoe过表达质粒转染子宫内膜癌HEC-1B细胞... 详细信息

目的研究载脂蛋白E(apoe)在子宫内膜癌转移中的具体作用及分子调控机制。方法子宫内膜癌HEC-1B细胞常规培养,空白对照组siRNA以及apoe靶向的siRNA转染子宫内膜癌HEC-1B细胞,以及采用空载质粒和apoe过表达质粒转染子宫内膜癌HEC-1B细胞,分为空白对照组siCtrl、siapoe组、空载质粒组、apoe过表达质粒组。利用划痕实验和Transwell实验检测子宫内膜癌细胞的迁移能力,通过MTT实验及流式细胞术验证apoe对子宫内膜癌细胞增殖能力的影响,使用Hoechst染色法检测干扰apoe后HEC-1B细胞的凋亡情况,采用qPCR、Western blotting观察ERK/MMP9信号通路的变化;通过免疫组化的方法分析apoe的表达与子宫内膜癌组织分化程度的相关性。结果划痕实验和Transwell小室实验结果显示,与空白对照组相比,转染了siapoe的HEC-1B细胞的迁移能力均明显下降(Papoe能显著促进子宫内膜癌细胞HEC-1B的迁移能力(Papoe对细胞增殖无影响。Hoechst染色实验结果表明干扰apoe后HEC-1B细胞的凋亡能力没有受到影响。Western blotting结果显示敲低apoe能够降低子宫内膜癌细胞中MMP9的蛋白表达水平(Papoe能使细胞内MMP9的蛋白水平升高(Papoe对MMP9的促进作用(Papoe在子宫内膜癌组织的表达水平比癌旁组织高。结论 apoe在子宫内膜癌组织中呈高表达,apoe可通过影响ERK的磷酸化,促进子宫内膜癌细胞中MMP9的表达,促进子宫内膜癌细胞的迁移。

关键词： apoe ERK 子宫内膜癌细胞迁移

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Apolipoprotein E, amyloid-beta, and neuroinflammation in Alzheimer's disease

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Neuroscience Bulletin 2014年第2期30卷 317-330页

作者： Evan Dorey Nina Chang Qing Yan Liu Ze Yang Wandong Zhang Faculty of Medicine University of Ottawa Human Health Therapeutics National Research Council of Canada Institute of Geriatrics/Beijing Hospital Ministry of Health of China

Alzheimer＇s disease （AD） is characterized by the accumulation and deposition of amyloid-beta （Aβ） peptides in the brain. Neuroinflammation occurs in the AD brain and plays a critical role in the neurodegenerative pathology. Particularly, Aβ evokes an inflammatory response that leads to synaptic dysfunction, neuronal death, and neurodegeneration. Apolipoprotein E （apoe） proteins are involved in cholesterol transport, Aβ binding and clearance, and synaptic functions in the brain. The apoe4 isoform is a key risk factor for AD, while the apoe2 isoform has a neuroprotective effect. However, studies have reached different conclusions about the roles of the isoforms; some show that both apoe3 and apoe4 have anti-inflammatory effects, while others show that apoe4 causes a predisposition to inflammation or promotes an inflammatory response following lipopolysaccharide treatment. These discrepancies may result from the differences in models, cell types, experimental conditions, and inflammatory stimuli used. Further, little was known about the role of apoe isoforms in the Aβ-induced inflammatory response and in the neuroinflammation of AD. Our recent work showed that apoe isoforms differentially regulate and modify the Aβ-induced inflammatory response in neural cells, with apoe2 suppressing and apoe4 promoting the response. In this article, we review the roles, mechanisms, and interrelations among Aβ, apoe, and neuroinflammation in AD.

关键词： apoe Alzheimer＇s disease Aβ neuroinflammation

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The Involvement of Lipids in Alzheimer's Disease

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Journal of Genetics and Genomics 2014年第5期41卷 261-274页

作者： Wei Ling Florence Lim Ian James Martins Ralph Nigel Martins School of Medical Sciences Edith Cowan University Centre of Excellence in Alzheimer's Disease Research and Care McCusker Foundation for Alzheimer's Disease Research Inc. Suite 22 Hollywood Medical Centre School of Psychiatry and Clinical Neurosciences The University of Western Australia

It has been estimated that Alzheimer＇s disease （AD）, the most common form of dementia, will affect approximately 81 million individuals by 2040. To date, the actual cause and cascade of events in the progression of this disease have not been fully determined. Furthermore, there is currently no definitive blood test or simple diagnostic method for AD. Considerable efforts have been put into proteomic approaches to develop a diagnostic blood test, but to date these efforts have not been successful. More recently, there has been a stronger focus on lipidomic studies in the hope of increasing our understanding of the underlying mechanisms leading to AD and developing an AD blood test. It is well known that the strongest genetic risk factor for AD is the e4 variant of apolipoprotein E （apoe）. Evidence suggests that the apoe protein, a major lipid transporter, plays a key role in the pathogenesis of AD, and its role in both normal and aberrant lipid metabolism warrants further extensive investigation. Here, we review apoe-lipid interactions, as well as the roles that lipids may play in the pathogenesis of AD.

关键词： Alzheimer＇s disease Lipids apoe Oxysterols Inflammation

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apoe与骨质疏松症相关性的研究进展

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中国骨质疏松杂志 2023年第10期29卷 1544-1549页

作者：赵付琳罗祥魏强张德茂白明茹四川大学华西口腔医院口腔疾病国家重点实验室四川成都610041 四川大学华西基础医学与法医学学院生物医学工程研究所四川成都610041 四川大学华西口腔医院四川成都610041

骨质疏松症(osteoporosis,OP)作为一种比较常见的骨代谢疾病,与高血脂症间存在着一定的关联,临床上同时患有这两种疾病的现象比较常见。当骨吸收增加而骨形成减少时,骨代谢失衡,就会发生OP。载脂蛋白E(apoe)是血浆中主要的载脂蛋白之一,... 详细信息

骨质疏松症(osteoporosis,OP)作为一种比较常见的骨代谢疾病,与高血脂症间存在着一定的关联,临床上同时患有这两种疾病的现象比较常见。当骨吸收增加而骨形成减少时,骨代谢失衡,就会发生OP。载脂蛋白E(apoe)是血浆中主要的载脂蛋白之一,apoe功能异常是引起高血脂症的关键。近年来依托apoe基因敲除鼠模型,在apoe调节血脂机制及高脂血症与OP的发生过程相关性的研究有了诸多新发现,拓宽了固有认知。本文主要汇总了apoe近5年与骨相关的研究,分析其影响OP的发生过程的机制,从宏观的血脂和细胞层面到微观的氧化应激和炎症层面,总结了apoe对骨代谢的重要调节作用,以期为后续研究、新药物筛选及临床应用提供参考依据。

关键词： apoe 骨质疏松炎症因子氧化应激

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A multiple-reaction-monitoring mass spectrometric method for simultaneous quantitative analysis of five plasma apolipoproteins

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Science China Chemistry 2014年第5期57卷 723-731页

作者： LI WenWen WANG QuanHui CHEN JianJun ZHOU Jian ZHOU XinYu XIE Peng Department of Neurology the First Affiliated Hospital Chongqing Medical University Chongqing Key Laboratory of Neurobiology Institute of Neuroscience Chongqing Medical University Beijing Institute of Genomics Chinese Academy of Sciences BGI-Shenzhen

A multiplexed targeted proteomic assay using a mTRAQ-MRM/MS-based approach was developed and assessed to systematically quantify the relative expressions of five candidate plasma apolipoproteins that have been previously shown to be dysregulated in neuropsychiatric disorders and cognitive dysfunction:apolipoprotein H(APOH),apolipoprotein J(APOJ),apolipoprotein A4(APOA4),apolipoprotein E(apoe),and apolipoprotein D(APOD).The peptides and transitions of each APO were carefully selected according to the tandem MS signals acquired on a TripleTOFTM 5600,followed by optimization of the declustering potential and collision energy voltages for transitions on a QTRAP 5500.Our results showed that the collision energies of mTRAQ-labeled peptides were approximately 15%–20%higher than corresponding non-labeled peptides.Through optimized transitions and parameters,we analyzed the relative abundances of the five APOs in human plasma with and without depletion of high abundant proteins.The results indicated that the MRM signals of four target APOs were significantly increased after depletion,while the MRM signal of one APO,APOD,was decreased.Furthermore,the relative abundances of the five target APOs in healthy human plasma were stable,and the ranking of these proteins according to their MS responses changed slightly.Therefore,we deduced that the rank order of the MS signals for these target proteins can be developed as a diagnostic signature for diseased plasma.

关键词：载脂蛋白H 人血浆多反应监测定量分析质谱法 apoe 蛋白质组认知功能障碍

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apoe调控神经胶质细胞发育的功能研究

ApoE调控神经胶质细胞发育的功能研究

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作者：徐颖杭州师范大学

学位级别：硕士

中枢神经系统的胶质细胞由星形胶质细胞(astrocyte,AS)、少突胶质细胞(oligodendrocyte,OLs)和小胶质细胞组成。它们为神经元提供结构和代谢支持,参与损伤修复和吞噬作用等。它们的发育异常可导致神经元功能紊乱和一系列神经退行性疾病... 详细信息

中枢神经系统的胶质细胞由星形胶质细胞(astrocyte,AS)、少突胶质细胞(oligodendrocyte,OLs)和小胶质细胞组成。它们为神经元提供结构和代谢支持,参与损伤修复和吞噬作用等。它们的发育异常可导致神经元功能紊乱和一系列神经退行性疾病。载脂蛋白Apolipoprotein E(Apo E)是阿尔茨海默病(Alzheimer’s disease,AD)和动脉硬化的风险基因。尽管apoe主要是由AS在大脑中分泌,但以前的研究主要集中在神经元的变化上,apoe在胶质发育和神经退行性疾病中的作用仍有待确定。在这篇论文中,我们分析了小鼠脊髓的单细胞测序,确定了24个在AS中高度表达的基因。这些基因的表达通过RNA原位杂交进行了验证。特别是,我们结合分子和遗传学方法,研究了载脂蛋白在胶质细胞发育中的表达和功能。我们发现:(1)在胶质细胞发育过程中,Apo E由AS和激活的小胶质细胞表达。(2)纤维性AS在P7、P15和P30时在Apo E-KO小鼠中减少。(3)虽然P7时期OLs的发育在Apo E-KO小鼠中没有受到影响,但在P15和P30时OLs分化和髓鞘形成明显增加。(4)从P7到P30,在Apo E-KO小鼠中没有观察到IBA1小胶质细胞的明显变化。以上结果揭示Apo E不仅促进了AS的发育,还抑制了OLs的发育。也说明了在Apo E-KO小鼠发育的早期就出现了胶质细胞发育异常,并可能与晚期神经系统疾病有关。虽然已知载脂蛋白可调节大脑胆固醇平衡,但仍不清楚AS如何影响OLs分化和髓鞘发育。我们将探讨载脂蛋白参与的胆固醇代谢如何调节胶质细胞的发育。这项研究将提高我们对胶质细胞相关神经系统疾病的病理学的理解,并促进其早期诊断和治疗。

关键词： apoe 少突胶质细胞星形胶质细胞髓鞘形成

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