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Neural Regeneration Research 2012年第14期7卷 1088-1094页

作者： Liangyu Zou Haiyan Qin Yitao He Heming Huang Yi Lu Xiaofan Chu Department of Neurology Shenzhen People's HospitalSecond Clinical CollegeJinan UniversityShenzhen 518020Guangdong ProvinceChina

Cerebral ischemia was induced using photothrombosis 1 hour after intraperitoneal injection of the p38 mitogen-activated protein kinase （MAPK） inhibitor $B239063 into Swedish mutant amyloid precursor protein （APP/SWE） transgenic and non-transgenic mice. The number of surviving neurons in the penumbra was quantified using Nissl staining, and the activity of p38 MAPKs was measured by western blotting. The number of surviving neurons in the penumbra was significantly reduced in APP/SWE transgenic mice compared with non-transgenic controls 7 days after cerebral ischemia, but the activity of p38 MAPKs was significantly elevated compared with the non-ischemic hemisphere in the APP/SWE transgenic mice. SB239063 prevented these changes. The APP/SWE mutation exacerbated ischemic brain injury, and this could be alleviated by inhibiting p38 MAPK activity.

关键词： cerebral ischemia amyloid precursor protein transgenic Alzheimer's disease p38mitogen-activated protein kinase SB239063 neural regeneration

Tetrahydroxy stilbene glucoside reduces the cognitive impairment and overexpression of amyloid precursor protein induced by aluminum exposure

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Neuroscience Bulletin 2009年第6期25卷 391-396页

作者：罗红波杨金升石向群付学峰杨期东兰州军区兰州总医院神经内科兰州730050 中南大学湘雅医院神经内科长沙410008

Objective Excessive aluminum （Al） exposure impairs neurocognitive function in humans and animals. Epidemiologic studies have shown a potential linkage between chronic Al exposure and Alzheimer’s disease. The present study aims to evaluate the effects of tetrahydroxy stilbene glucoside （TSG）, the extract from herbal medicine Polygoni Multiflori, on cognitive impairment and the over-expression of hippocampal amyloid precursor protein （APP） induced by chronic exposure to Al in rats. Methods Rats were treated with 0.3% aluminum chloride （AlCl3） prepared in the drinking water for 90 d. AlCl3-treated animals were then randomly assigned to receive vehicle, TSG （4 g/kg）, or Vitamin E （VE; 40 mg/kg） treatment for 5 months. VE served as a positive control. The effect of TSG was evaluated by passive avoidance task, and APP expression was evaluated by Western blotting. Results Following exposure to AlCl3 for 90 d, animals displayed a striking decrease （〉80%） in step-through latency in the passive avoidance task and a significant increase in the expression of APP in the hippocampus. Both TSG and VE significantly ameliorated the performance impairment in the passive avoidance task, and suppressed the over-expression of APP. Moreover, the effects of TSG, but not of VE, were in a time-dependent manner. Conclusion TSG may possess therapeutic effects against Alzheimer’s disease.

关键词： tetrahydroxy stilbene glucoside cognitive impairment amyloid precursor protein aluminum

Regulation of β cleavage of amyloid precursor protein

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Neuroscience Bulletin 2010年第5期26卷 417-427页

作者：王军锋路睿王以政中国科学院上海生命科学研究院神经科学研究所神经科学国家重点实验室上海200031

Alzheimer’s disease ranks the first cause for senile *** amyloid cascade is proposed to contribute to the pathogenesis of this *** this cascade,amyloid β peptide（Aβ）is produced through a sequential cleavage of amyloid precursor protein（APP）by β and γ secretases,while its cleavage by α secretase precludes Aβ production and generates neurotrophic sAPPα.Thus,enhancing α secretase activity or suppressing β and γ cleavage may reduce Aβ formation and ameliorate the pathological process of the *** regulatory mechanisms of APP cleavage have been established. The present review mainly summarizes the signaling pathways pertinent to the regulation of APP β cleavage.

关键词： Alzheimer’s disease amyloid β peptide amyloid precursor protein β secretase

Estrogen stimulates release of secreted amyloid precursor protein from primary rat cortical neurons via protein kinase C pathway

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Acta Pharmacologica Sinica 2005年第2期26卷 171-176页

作者： Sun ZHANG~2,Ying HUANG~2,Yi-chun ZHU~2,Tai YAO~(2,3,4)~2Department of Physiology and Pathophysiology ~3State Key Laboratory for Medical Neurobiology,Shanghai Medical College of FudanUniversity,Shanghai 200032,China Department of Physiology and Pathophysiology Shanghai Medical College of FudanUniversity Shanghai 200032 China

Aim:To investigate the mechanism of the action of estrogen,which stimulates therelease of secreted amyloid precursor protein α(sAPPα)and decreases the gen-eration of amyloid-β protein(Aβ),a dominant component in senile plaques in thebrains of Alzheimer's disease ***:Experiments were carried out inprimary rat cortical neurons,and Western blot was used to detect sAPPα in aculture medium and the total amount of cellular amyloid precursor protein(APP)***:17β-Estradiol(but not 17α-estradiol)and β-estradiol 6-(O-carboxymethyl)oxime:BSA increased the secretion of sAPPα and this effect wasblocked by protein kinase C(PKC)inhibitor calphostin C,but not by the classicalestrogen receptor antagonist ICI 182,***,17β-estradiol did not alterthe synthesis of cellular ***:The effect of 17β-estradiol on sAPPαsecretion is likely mediated through the membrane binding sites,and needs mo-lecular configuration specificity of the ***,the action of the PKC-dependent pathway might be involved in estrogen-induced sAPPα secretion.

关键词： Alzheimer disease estrogen amyloid precursor protein estrogen receptors protein kinase C

Effects of Gingko biloba leaf extract on learning, memory, and hippocampal amyloid precursor protein mRNA expressions in diabetic rats

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Neural Regeneration Research 2008年第1期3卷 29-32页

作者： Xiaofan Zhang Bo Liang Zhifeng Liang Jun Lin Grade 2003 of Pharmaceutical School Guangxi Medical University Nanning 530021 Guangxi Zhuang Autonomous Region China Department of Physiology Guangxi Medical University Nanning 530021 Guangxi Zhuang Autonomous Region China Department of Pharmacology Pharmaceutical School Guangxi Medical University Nanning 530021 Guangxi Zhuang Autonomous Region China

BACKGROUND： The mechanisms of brain injury Following diabetes could be related to amyloid precursor protein （APP） mRNA overexpression. Studies have shown that Gingko biloba leaf extract （EGb） is effective in promoting functional recovery of the brain after traumatic injury. EGb is also effective in improving central nervous system plasticity and learning and memory functions of the elderly. OBJECTIVE： To study the effects of EGb on learning and memory, as well as hippocampal APP mRNA expression in the brains of diabetic rats, using Morris water maze behavioral testing and reverse transcription polymerase chain reaction （RT-PCR）, respectively. DESIGN： Complete random design, controlled experimental study. SETTING： Department of Pharmacology, Pharmaceutical School, Guangxi Medical University. MATERIALS： A total of 70 male Wistar rats （180-220 g）, 8 weeks old and specific pathogen free, were used for this study. GbE （containing 24.8% flavone glycosides and 6.2% diterpene lactone） was purchased from Guilin Sitejia Natural Plants Pharmaceutical Factory （Guangxi Province, Lot NO. 200405）. Streptozotocin was purchased from Sigma （USA）. Protamine zinc insulin injection was purchased from WANBANG Biochemical Pharmaceutical Co., Ltd. （Xuzhou Jiangsu, China）. METHODS： The experiment was performed in the Experimental Center of Guangxi Medical University from March to October 2005.（1） Experimental intervention： 70 rats were divided randomly into normal control group, diabetic model group （DM group）, diabetic model ＋10 μ g/kg insulin group （DM ＋ Ins group）, diabetic model ＋ 100 mg/kg ginkgo leaf extract group （DM ＋ EGb high-dose group）, and diabetic model ＋ 50 mg/kg ginkgo leaf extract group （DM ＋ EGb low-dose group）; there were 14 rats in each group. Rats with an intraperitoneal （i.p.） injection of citrate buffer solution （pH 4.4） served as the control group. To establish the diabetes model, rats were treated with i.p. injection of 55 mg/kg streptozotocin. Insulin （10 U/kg） was

关键词： Gingko biloba leave extract diabetes hippocampus amyloid precursor protein

Divalent cation tolerance protein binds to β-secretase and inhibits the processing of amyloid precursor protein

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Neural Regeneration Research 2013年第11期8卷 991-999页

作者： Runzhong Liu Haibo Hou Xuelian Yi Shanwen Wu Huan Zeng State Key Laboratory of Cellular Stress Biology Department of Biomedical Sciences School of Life Sciences Xiamen University Xiamen Maternal and Child Health Hospital

The deposition of amyloid-beta is a pathological hallmark of Alzheimer＇s disease, amyloid-beta is derived from amyloid precursor protein through sequential proteolytic cleavages by β-secretase （beta-site amyloid precursor protein-cleaving enzyme 1） and r-secretase. To further elucidate the roles of beta-site amyloid precursor protein-cleaving enzyme 1 in the development of AIzheimer＇s disease, a yeast two-hybrid system was used to screen a human embryonic brain cDNA library for proteins directly interacting with the intracellular domain of beta-site amyloid precursor protein-cleaving enzyme 1. A potential beta-site amyloid precursor protein-cleaving enzyme 1- interacting protein identified from the positive clones was divalent cation tolerance protein. Immunoprecipitation studies in the neuroblastoma cell line N2a showed that exogenous divalent cation tolerance protein interacts with endogenous beta-site amyloid precursor protein-cleaving enzyme 1. The overexpression of divalent cation tolerance protein did not affect beta-site amyloid precursor protein-cleaving enzyme 1 protein levels, but led to increased amyloid precursor protein levels in N2a/APP695 cells, with a concomitant reduction in the processing product amyloid precursor protein C-terminal fragment, indicating that divalent cation tolerance protein inhibits the processing of amyloid precursor protein. Our experimental findings suggest that divalent cation tolerance protein negatively regulates the function of beta-site amyloid precursor protein-cleaving enzyme 1. Thus, divalent cation tolerance protein could play a protective role in Alzheimer＇s disease.

关键词： neural regeneration brain injury neurodegenerative diseases Alzheimer's disease amyloid-betaβ-secretase amyloid precursor protein beta-site amyloid precursor protein-cleaving enzyme 1 interaction amyloid precursor protein C-terminal fragment western blot yeast two-hybridization grants-supported paper neuroregeneration

Schisandrin B protects PC12 cells by decreasing the expression of amyloid precursor protein and vacuolar protein sorting 35

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Neural Regeneration Research 2012年第9期7卷 652-658页

作者： Mingmin Yan Shanping Mao Huimin Dong Baohui Liu Qian Zhang Gaofeng Pan Zhiping Fu Department of Neurology Renmin Hospital Wuhan University Wuhan 430060 Hubei Province China Department of Neurosurgery Renmin Hospital Wuhan University Wuhan 430060 Hubei Province China

PC12 cell injury was induced using 20 μM amyloid β-protein 25-35 to establish a model of Alzheimer＇s disease. The cells were then treated with 5, 10, and 25 μM Schisandrin B. Methylthiazolyldiphenyl-tetrazolium bromide assays and Hoechst 33342 staining results showed that with increasing Schisandrin B concentration, the survival rate of PC12 cells injured by amyloid β-protein 25-35 gradually increased and the rate of apoptosis gradually decreased. Reverse transcription-PCR, immunocytochemical staining and western blot results showed that with increasing Schisandrin B concentration, the mRNA and protein expression of vacuolar protein sorting 35 and amyloid precursor protein were gradually decreased. Vacuolar protein sorting 35 and amyloid precursor protein showed a consistent trend for change. These findings suggest that 5, 10, and 25 μM Schisandrin B antagonizes the cellular injury induced by amyloid β-protein 25-35 in a dose-dependent manner. This may be caused by decreasing the expression of vacuolar protein sorting 35 and amyloid precursor protein.

关键词： Schisandrin B PC12 cells amyloid β-protein 25-35 amyloid precursor protein vacuolar protein sorting 35 neural protection

Observation of amyloid precursor protein cleavage and Aβ generation in living cells by using multiphoton laser scanning microscopy

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Neuroscience Bulletin 2007年第5期23卷 256-262页

作者：李晓晴张苏明杨华静张智红华中科技大学同济医学院附属同济医院神经内科武汉430030 华中科技大学生物医学光子学教育部重点实验室武汉430030

Objective To investigate the proteolytic mechanism of amyloid precursor protein （APP） and to explore amyloidbeta （Aβ） generation in living neurons. Methods DNA fragments were amplified by PCR or synthesized. The four fragments, CFP, 54bp, YFP and C99 were ligated into pcDNA3.0 vector to construct the recombinant plasmids pcDNA3.0-CFP-54bp- YFP and pcDNA3.0-CFP-54bp-YFP-C99. The SH-SY5Y cells were transiently transfected with pcDNA3.0-CFP-54bp-YFP or pcDNA3.0-CFP-54bp-YFP-C99. The expression of fusion gene was examined under a multiphoton laser scanning microscope. Fluorescence resonance energy transfer （FRET） was used to measure the β cleavage and γ cleavage of APE Aβ generation was confirmed by immunocytochemistry and multiphoton laser scanning microscopy. Cell viability was tested by MTT assay at different time points. Results （1） The double restriction endonuclease digestion and sequencing analysis confirmed the authenticity of the recombinant plasmids pcDNA3.0-CFP-54bp-YFP and pcDNA3.0-CFP-54bp- YFP-C99. （2） Blue and yellow fluorescences were detected in the transfected cells. （3） FRET occurred in pcDNA3.0-CFP- 54bp-YFP-transfected cells but not in pcDNA3.0-CFP-54bp-YFP-C99-transfected cells. （4） Aβ was produced in the pcDNA3.0- CFP-54bp-YFP-C99 transfected cells. （5） Aβ-deposition was widespread in the cell. （6） Cell viability decreased along with the intracellular Aβ deposition. Conclusion C99 is important for the APP β cleavage. Aβ may be generated and deposited in cells at the early stage of Alzheimer＇s disease. Intracellular Aβ accumulation brings deleterious effects on cells.

关键词： amyloid precursor protein amyloid beta protein beta-cleavage fluorescence resonance energy transfer

Induction of Silencing Effect of Swedish Mutant amyloid precursor protein by RNA interference

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2006年第4期26卷 399-401页

作者：邱昕陈国华潘纪安陈宇张苏明 Department of Neurology Integrated Traditional Chinese and Western Medicine HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430022China Modern Virology Research Center College of Life SciencesWuhan UniversityWuhan430072China Department of Neurology Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China

Summary： Over-expression of APP and Swedish mutation could cause some familial early onset AD. In this study, a primary screening was conducted of effective small interference RNAs （siRNAs） targeted wild type APP （APPwt） and Swedish mutant APP （APPswe）. One siRNA targeting APPwt and the other siRNA targeting APPswe were designed, All these siRNAs were endogenously expressed by siRNAs expressing plasmids, COS-7 cells were transiently co-transfected with APP-GFP recombinant plasmids and siRNA expression vector, The silencing effect of each siRNA was quantitatively assessed by the level of expression of green fluorescent protein （GFP）. It was found that the siRNAs silenced APPwt and APPswe to different degrees, siRNA directed against APPswe was more effective in suppressing the expression of fusion gene of APPswe than that of APPwt. The silencing effect of siRNA directed against APPswe indicating allele-specific silencing property of the siRNAs. Therefore, siRNAs directed against APP play an important role both in the therapeutic study of Alzheimer disease and functional exploration ofAPP gene.

关键词： amyloid precursor protein small interference RNA wild type APP Swedish mutant APP

Amino-terminal fragment of human amyloid precursor protein in pichia pastoris

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Amino-terminal fragment of human amyloid precursor protein i...