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Mutations of beta-amyloid precursor protein alter the consequence of Alzheimer's disease pathogenesis

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Neural Regeneration Research 2019年第4期14卷 658-665页

作者： Nuo-Min Li Ke-Fu Liu Yun-Jie Qiu Huan-Huan Zhang hiroshi nakanishi Hong Qing School of Life Science Beijing Institute of Technology Department of Aging Science and Pharmacology Faculty of Dental Science Kyushu University

Alzheimer's disease is pathologically defined by accumulation of extracellular amyloid-β(Aβ). Approximately 25 mutations in β-amyloid precursor protein(APP) are pathogenic and cause autosomal dominant Alzheimer's disease. To date, the mechanism underlying the effect of APP mutation on Aβ generation is unclear. Therefore, investigating the mechanism of APP mutation on Alzheimer's disease may help understanding of disease pathogenesis. Thus, APP mutations(A673T, A673 V, E682 K, E693 G, and E693Q) were transiently co-transfected into human embryonic kidney cells. Western blot assay was used to detect expression levels of APP, beta-secretase 1, and presenilin 1 in cells. Enzyme-linked immunosorbent assay was performed to determine Aβ_(1–40) and Aβ_(1–42) levels. Liquid chromatography-tandem mass chromatography was used to examine VVIAT, FLF, ITL, VIV, IAT, VIT, TVI, and VVIA peptide levels. Immunofluorescence staining was performed to measure APP and early endosome antigen 1 immunoreactivity. Our results show that the protective A673 T mutation decreases Aβ_(42)/Aβ_(40) rate by downregulating IAT and upregulating VVIA levels. Pathogenic A673 V, E682 K, and E693 Q mutations promote Aβ_(42)/Aβ_(40) rate by increasing levels of CTF99, Aβ_(42), Aβ_(40), and IAT, and decreasing VVIA levels. Pathogenic E693 G mutation shows no significant change in Aβ_(42)/Aβ_(40) ratio because of inhibition of γ-secretase activity. APP mutations can change location from the cell surface to early endosomes. Our findings confirm that certain APP mutations accelerate Aβ generation by affecting the long Aβ cleavage pathway and increasing Aβ_(42/40) rate, thereby resulting in Alzheimer's disease.

关键词： nerve regeneration Alzheimer’s disease β-amyloid precursor protein amyloidβ APP mutations liquid chromatography-tandem mass chromatography cellular localization long Aβ neural regeneration

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NMR Studies on the Interactions between Proteins and Antigen Peptides in MHC Class I Protein Complex of Immune System

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NMR Studies on the Interactions between Proteins and Antigen...

第十三届全国波谱学学术会议

作者： hiroshi nakanishi Biological Information Research Center National Institute of Advanced Science and IndustryTsukuba Central 61-1HigashiTsukubaIbaraki 305-8566Japan

＜正＞A major histocompatibility complex（MHC）class Ⅰ protein consists of heavy chain which has α-1,2,3 domains and light chain（β2,microgiobulin,β2 m）.An antigen peptide binds to a peptide binding groove in the... 详细信息

关键词： NMR interaction between peptide and protein MHC Class I protein Antigen peptides line broadening Transfer-NOE 15N and D enriched protein β2-microglobulin

Super MALDI-TOF-MS Method of New Detection of Larger Molecular Ions by Using Super Conducting Sensor

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Super MALDI-TOF-MS Method of New Detection of Larger Molecul...

第五届全国化学生物学学术会议

作者： Masataka Ohkubo hiroshi nakanishi Research Institute of Instrumentation Frontier National Institute of Advanced Industrial Science and TechnologyTsukuba central 21-1-1UmezonoTsukubaIbaraki 305-8568Japan Research Institute of Instrumentation Frontier National Institute of Advanced Industrial Science and TechnologyTsukuba central 21-1-1UmezonoTsukubaIbaraki 305-8568Japan

＜正＞MALDI-TOF-MS is used at the present stage to measure the total molecular ions and the fragment ions,which are relatively smaller *** highest molecular weights at the present level are estimated to ca.450,000 *** the present spectrometer with the detector by the mulch-channel plate system,the detections of larger molecules become more difficult as they are larger molecules.

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The Critical Role of IL-10 in the Anti-neuroinflammatory and Anti-oxidative Effects of Rheum Tanguticum on Activated Microglia

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神经药理学报 2018年第2期 26-27页

作者： MENG Jie NI Jun-jun WU Zhou ZHU Ai-qin QING Hong hiroshi nakanishi Department of Aging Science and Pharmacology Faculty of Dental SciencesKyushu University OBT Research Center Faculty of Dental SciencesKyushu University Institution of Geriatric Qinghai Provincial Hospital School of Life Science Beijing Institute of Technology

Objective:Rheum tanguticum Maxim. ex Balf.（Rt）,a traditional Tibetan medicine,is known to exert various bioactivities,including anti-inflammatory and anti-oxidative activities. The present study was conducted to investigate anti-inflammatory and anti-oxidative effects of Rt on activated microglia. Methods:（1）MG6 microglial cell line,primary microglia and mice brain slices culture were stimulated by chromogranin A（CGA）,an endogenous microglia activator,to induce proinflammation and oxidation. The anti-inflammatory and anti-oxidative effects of Rt were examined by q-PCR,western blotting and ELISA by checking inflammatory and oxidative molecules,including IL-1β,tumor necrosis factor-α,IL-10 and nitric oxide.（2）Investigation of the involvement of IL-10 in the anti-inflammatory effects of Rt on inflammatory responses of microglia by using neutralizing antibodies against IL-10. Pro-inflammatory molecules expression were checked by q-PCR.（3）Examination of the effects of major components of Rt(aloe-emodin,（+）-cathechin,piceatannol chrisophanol,physcion,β-sitosterol and emodin) on the IL-10 mRNA expression in MG6 cells. Results:（1）The mean mRNA expression levels of TNF-α,IL-1β and i NOS were significantly increased in MG6 cells at 24 h after stimulation with CGA. Rt significantly suppressed the mean mRNA expression levels of TNF-α,IL-1βand i NOS in GGA-stimulated MG6 cells. Furthermore,the production of IL-1β and NO metabolites in the culture medium of MG6 cells were assessed by using ELISA and NO;/NO;assay,respectively. The mean levels of IL-1β and NO;/NO;significantly increased in the culture medium of MG6 cells at 24 h after treatment with CGA. Rt also significantly decreased the mean levels of IL-1β and NO;/NO;in the culture medium of MG6 cells. The mean protein level of IL-1β significantly increased in the organotypic hippocampal slice cultures at 48 h after stimulation with CGA(10 nmol·L;). Rt significantly suppressed the mean protein level of IL-1β in CGA-stimulated o

关键词： IL The Critical Role of IL-10 in the Anti-neuroinflammatory and Anti-oxidative Effects of Rheum Tanguticum on Activated Microglia NOS TNF

Increased Expression and Altered Subcellular Distribution of Cathepsin B in Microglia Induces Cognitive Impairment through Oxidative Stress and Inflammatory Response in Mice

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神经药理学报 2018年第2期 27-28页

作者： NI Jun-jun WU Zhou Veronika Stoka Christoph Peters QING Hong Vito Turk hiroshi nakanishi Department of Aging Science and Pharmacology Faculty of Dental ScienceKyushu University Department of Biochemistry and Molecular and Structural Biology J.Stefan Institute Institute für Molekulare Medizin und Zellforshung Albert-Ludwigs-Universit?t Freiburg Beijing Key Laboratory of Separation and Analysis in Biomedical and Pharmaceuticals Department of Biomedical EngineeringSchool of Life ScienceBeijing Institute of Technology

Objective:During normal aging,innate immunity progresses to a chronic state. However,how oxidative stress and chronic neuroinflammation arise during aging remain unclear. In this study,we intended to demonstrate the novel function of Cathepsin B（ CatB） in the age related oxidative stress and chronic neuroinflammation. Methods:（1）2 month-old and 20 month-old wild-type and CatB;mice were used for learning and memory tests by step through passive avoidance tests. The cumulative potentiation of the field excitatory postsynaptic potential（ f EPSP） slope and dendritic spine density were also examined.（2）Inflammation were examined by immunoblotting of interleukin-1β（ IL-1β）,tumor necrosis factor-α（ TNF-α） and inducible nitric oxide synthase（ i NOS）,and oxidative stress were examined by checking the level of 8-oxo-7,8-dihydro-2’-deoxyguanosine（ 8-oxo-d G） and 4-hydroxynonenal（ 4-HNE） in the hippocampal lysate of 2 month-old and 20 month-old wild-type and CatB;mice.（3）Intra-lateral ventricle transplantation of CatB over-expressed microglia in middleaged mice,learning and memory were examined by Y-maze and novel objective tests. Results:（1）The retention latencies of both aged groups were significantly longer than those in the acquisition trial. The retention latency of four consecutive trials was significantly longer in aged CatB;mice than in aged wild-type mice. Furthermore,the mean relative f EPSP slope measured at 30 min after stimulationwith 25,50 and 100 Hz in the aged CatB;mice was significantly larger than that in the aged wildtype mice. The mean dendritic spine density of CA1 neurons in the aged CatB;mice was significantly larger than that in the aged wild-type mice.（2）The mean levels of CatB,i NOS,IL-1β and TNF-α in the hippocampus were significantly higher in aged wild-type mice than in younger animals. Furthermore,their mean levels in the hippocampus of aged CatB;mice were significantly lower than those in aged wild-type mice. The mean amounts of these oxidative ma

关键词： Increased Expression and Altered Subcellular Distribution of Cathepsin B in Microglia Induces Cognitive Impairment through Oxidative Stress and Inflammatory Response in Mice HNE

Conformational effects of serine phosphorylation in the C-terminal of c-Fos

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Conformational effects of serine phosphorylation in the C-te...

第六届全国磷化学化工学术讨论会

作者：罗施中李艳梅崔立平强伟赵玉芬 hiroshi ABE 秦旭荣 hiroshi nakanishi Bioorganic Phosphorus Chemistry Laboratory Department of ChemistrySchool of Life Science and EngineeringTsinghua UniversityBeijing 100084CHINA Biological Information Research Center National Institute Advanced Industry Science & Technology AISTCentral 61-1HigashiTsukuba305-8568Japan

Proteo-oncogene c-fos encodes a nuclear phosphoprotein (c-Fos) of 380 amino acids that can modulate the transciption of other genes either by transactivation or by transreperssion (1).Its viral oncogen v-fos encodes the v-Fos protein (381 amino acids) that shares the first 332 amino acids with the c-Fos protein (with five single amino-acid changes),but differs at C terminal (2).It has been previously reported that the c-Fos protein undergoes mores extensive post-translational modification than *** major modification of the c-Fos protein involves serine phosphoesterification of sites in the extreme C-terminal (3).c-Fos is a substrate for two families of highly conserved,growth-regulated protein serine/threonine kinase,the mitogen-activated protein kinase (MAP kinase) and its downstream substrate,the 90 kDa-ribosomal S6 kinase (RSK).These kinases phosphorylate c-Fos in a cooperative manner,and the target sites for RSK and MAP kinase are localized to serine 362 and 374 (rat),respectively (4).Phosphorylation of the C-terminal of c-Fos protein affects its transactivation properties and provides evidence for novel regulatory mechanisms that may contribute to biologic specificities of the AP-1 transcription complex (5).

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超塑化剂与水泥流动性能评估

商品混凝土 2007年第1期 67-73页

作者： Kazuo Yamada Takumi Sugamata hiroshi nakanishi 李蓉

为获得持久的混凝土结构,最重要的一步就是混凝土的无损浇注。在过去的十几年里,混凝土材料间的兼容性是控制无损浇注混凝土的工作性的重要问题,这一课题备受关注。每位工程师都希望有可靠的方法检测超塑化剂与水泥的流动性能。在这篇... 详细信息

为获得持久的混凝土结构,最重要的一步就是混凝土的无损浇注。在过去的十几年里,混凝土材料间的兼容性是控制无损浇注混凝土的工作性的重要问题,这一课题备受关注。每位工程师都希望有可靠的方法检测超塑化剂与水泥的流动性能。在这篇文章中,我们从基本原理着眼对检测流动性能的方法进行了论述。重要的一点就是超塑性混凝土的变形性质。当新拌混凝土均质性地变形时,混凝土拌和物的工作性可以被超塑化剂的一个基本理论所解释,也就是,流动性与水化物的表面积超塑化剂吸附量成正比关系。而且,超塑化剂与水泥的流动性检测还应考虑水灰比和材料混合程序等混凝土的实际情况。

关键词：超塑化剂流动性能混凝土拌和物混凝土材料扩展度塑性混凝土坍落混凝土结构混凝土工作性混

面神经离断后Cathepsin S基因敲除小鼠小胶质细胞反应的实验研究

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口腔医学研究 2015年第4期31卷 349-353,358页

作者：郝海鹏季振威中西博同济大学附属同济医院口腔科上海200065 日本九州大学齿学部加龄口腔科学分野

目的:研究面神经损伤后CS基因敲除(CS-/-)小鼠小胶质细胞的反应。方法:两种小鼠经脾分别注射CFDA,24h后离断右侧面神经。术后7d,取出含面神经核(FMN)的脑干进行切片,小胶质细胞和面神经元免疫荧光双重染色,作Westernblot分析,并进行CS... 详细信息

目的:研究面神经损伤后CS基因敲除(CS-/-)小鼠小胶质细胞的反应。方法:两种小鼠经脾分别注射CFDA,24h后离断右侧面神经。术后7d,取出含面神经核(FMN)的脑干进行切片,小胶质细胞和面神经元免疫荧光双重染色,作Westernblot分析,并进行CS、CB的RT-PCR定量分析。术后14d、50d,进行小胶质细胞免疫荧光双重染色。分别培养CS-/-和野生型小胶质细胞后进行ATP诱导小胶质细胞位移实验、游走实验、增殖实验。结果:神经离断后,CS和MMP-9在野生型小胶质细胞增生表达,而不出现在CS-/-小胶质细胞。CB仅在野生型面神经元内显著性增加。CFDA和CD3仅在野生型小鼠FMN内出现。CS和MMP-9在野生型小鼠FMN内明显增加,而CB的水平无变化,并且CB在CS-/-小鼠FMN内显著性增加。CS-/-小胶质细胞的位移和游走能力大幅降低,但增殖能力两者无明显差别。结论:面神经离断后,CS的缺失会使单核、淋巴细胞的动员游走能力受到损害,表现出了神经元毒性和吞噬作用。

关键词： CS基因敲除小鼠面神经离断小胶质细胞

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Ser262异常磷酸化对Tau蛋白结构及性质影响的研究

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Ser262异常磷酸化对Tau蛋白结构及性质影响的研究

第六届全国磷化学化工学术讨论会

作者：杜进堂李艳梅赵玉芬秦旭荣 Yasuko Ishizuka hiroshi nakanishi 清华大学化学系生命有机磷及化学生物学教育部重点实验室 National Institute of Advanced Industrial Science and Technology Biological Information Research Center 305-8566 Japan

阿尔兹海默病(AD)是一种神经退行性老年疾病,其患者的主要脑部特征为神经细胞外的老年斑和神经细胞内的神经纤维缠结。研究发现老年斑的主要成分为APP跨膜糖蛋白的异常剪切产物Aβ多肽,而神经纤维缠结的主要成分为异常磷酸化的微管相关...

阿尔兹海默病(AD)是一种神经退行性老年疾病,其患者的主要脑部特征为神经细胞外的老年斑和神经细胞内的神经纤维缠结。研究发现老年斑的主要成分为APP跨膜糖蛋白的异常剪切产物Aβ多肽,而神经纤维缠结的主要成分为异常磷酸化的微管相关蛋白Tau。微管相关蛋白Tau蛋白的基本功能是促进微管蛋白组装成微管并进一步稳定已组装的微管,微管在神经细胞内起着重要的作用,像信号的传输、营养物质的运输、维持细胞的形状等等。研究发现异常过度磷酸化的Tau蛋白丧失了促微管组装的活性,自身缠结为双股螺旋丝并进一步形成神经细胞内的神经纤维缠结。

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