正常增龄与AD患者额叶脑组织的比较蛋白质组学研究
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摘要
阿尔茨海默病(Alzheimer's disease,AD)是痴呆中最常见的一种,其发病机制及病理过程国内外学者通过人脑组织、动物模型、细胞模型等已经做了大量的研究,但其确切病因尚不明确。目前国内尚无AD相关的人脑蛋白质组学研究,本次实验利用中国人民解放军总医院老年医学研究所组织库收集的宝贵尸检病例标本进行研究。
本次实验主要包括三个部分:1)利用HE、免疫组织化学方法对病例进行筛选,根据病理诊断标准确诊后,结合临床诊断分组;2)通过荧光双向差异凝胶电泳技术分离蛋白点,并利用质谱进行蛋白点鉴定,搜库并分析蛋白点在AD发病机制中的意义。3)选择部分蛋白点进行western blotting验证,证明双向电泳的稳定性和准确性。
论文的第一部分是对AD的病理学筛查,利用国际公认的,发生特征性病理变化的抗体进行免疫组织化学染色,我们总共选择了anti-β-Amyloid/AT8/Synuclin/Ubiquitin四种抗体,根据淀粉样沉积、纤维缠结、神经毡等染色情况以及HE染色显示的神经元丢失等判断选择出AD病例,并利用Synuclin染色结果鉴别出同样具有痴呆表现的路易痴呆或帕金森病性痴呆。结合临床诊断标准最终选择出6例AD和6例正常对照,进行下一步的蛋白质组学研究。
论文的第二部分主要是:根据第一部分结论分成两组的病例,提取对应部位的新鲜脑组织蛋白,并进行荧光双向差异凝胶电泳,将获得的6副三通道荧光图输入配套的图像分析软件Image Master 2D Platinum、Image Quant、DeCyder(Version6.5)进行分析,分析得到的差异蛋白点进行质谱鉴定,明确差异蛋白点性质,搜库分析其与AD的关系。在本次实验中共发现18个差异蛋白点,鉴定了其中17个,得到14个蛋白质,其中有两种蛋白质是由不同的蛋白点鉴定所得。经查阅大量文献,发现获得的蛋白质多为氧化应激相关、骨架蛋白、分子伴侣蛋白等,有4种蛋白质未在以往的研究中报道,而另外的蛋白质的含量变化也与国外研究报道的不尽相同。
第三部分主要利用western blotting方法验证了热休克蛋白90α的含量变化,实验结果显示与双向电泳的结果一致,验证了双向电泳的稳定性和可靠性。
本研究为以后的AD发病机制的研究,为AD的诊断及治疗提供了新思路。
Alzheimer's disease(AD) is one of the most nomal dementias.A lot of work to identify the pathogenetic and pathologic progress of AD have been done by investigators in many countries using brain tissues of people,animal models and cell models.Now in China there is no study about proteomic of AD brain of people.We carried the study in the Geronotlogical Research Center of the general hospital of PLA with the samples conserved in paraffin wax and in refrigerator at -80℃.
The study included three parts:1)we selected the samples of AD and samples of control by HE stain and immunohistochemistry stain.Combining the clinical diagnosis,we designed the two groups after we obtained the pathologic diagnosis; 2) we isolated proteins of the two groups(AD group and control group) by fluorescence two-dimensional differential gel electrophoresis(2D-DIGE).Then identified the proteins by mass spectrometry and analyzed the association between the AD pathogenesy and the proteins.3)at the end,we validated part of the altered proteins by western blotting.
The first part:pathobiology.Anti-β-Amyloid,anti-AT8,anti-Ubiquitin were used to obtain the AD samples and contol samples,which are the most common antibodies admitted by people to characterize the AD's pathological changes.We used anti-Synuclin to exclude Lewy' body dementia and Parkinson's dementia. With all these pathological changes we at length defined two groups:AD group and control group with each group including 6 cases.
The second part:proteom study.After extracted protein from the cases of two groups,we ran the 2D-DIGE.The protein spots were analyzed by softwares of Image Master 2D Platinum,Image Quant and DeCyder(Version6.5) and then were identified by mass spectrometry.After searching in IPI HUMAN(v3.23) database,we obtained 14 different proteins.The different proteins are of oxidation, energy-related enzymes,and chaperonin et al.4 of the proteins have not been reported before in the studies of other investigators.Some alteration of protein level didn't correspond with that of the previous studies.
The third part of the study was to validate the results of 2D-DIGE with western blotting.We detected the altered level of HSP90αand the two results corresponded.This demonstrated the stability and reliability of the 2D-DIGE.
This study leads a new road to ascertain the pathogenesy of AD,and to find new diagnosis and therapy methods to AD.
本次实验主要包括三个部分:1)利用HE、免疫组织化学方法对病例进行筛选,根据病理诊断标准确诊后,结合临床诊断分组;2)通过荧光双向差异凝胶电泳技术分离蛋白点,并利用质谱进行蛋白点鉴定,搜库并分析蛋白点在AD发病机制中的意义。3)选择部分蛋白点进行western blotting验证,证明双向电泳的稳定性和准确性。
论文的第一部分是对AD的病理学筛查,利用国际公认的,发生特征性病理变化的抗体进行免疫组织化学染色,我们总共选择了anti-β-Amyloid/AT8/Synuclin/Ubiquitin四种抗体,根据淀粉样沉积、纤维缠结、神经毡等染色情况以及HE染色显示的神经元丢失等判断选择出AD病例,并利用Synuclin染色结果鉴别出同样具有痴呆表现的路易痴呆或帕金森病性痴呆。结合临床诊断标准最终选择出6例AD和6例正常对照,进行下一步的蛋白质组学研究。
论文的第二部分主要是:根据第一部分结论分成两组的病例,提取对应部位的新鲜脑组织蛋白,并进行荧光双向差异凝胶电泳,将获得的6副三通道荧光图输入配套的图像分析软件Image Master 2D Platinum、Image Quant、DeCyder(Version6.5)进行分析,分析得到的差异蛋白点进行质谱鉴定,明确差异蛋白点性质,搜库分析其与AD的关系。在本次实验中共发现18个差异蛋白点,鉴定了其中17个,得到14个蛋白质,其中有两种蛋白质是由不同的蛋白点鉴定所得。经查阅大量文献,发现获得的蛋白质多为氧化应激相关、骨架蛋白、分子伴侣蛋白等,有4种蛋白质未在以往的研究中报道,而另外的蛋白质的含量变化也与国外研究报道的不尽相同。
第三部分主要利用western blotting方法验证了热休克蛋白90α的含量变化,实验结果显示与双向电泳的结果一致,验证了双向电泳的稳定性和可靠性。
本研究为以后的AD发病机制的研究,为AD的诊断及治疗提供了新思路。
Alzheimer's disease(AD) is one of the most nomal dementias.A lot of work to identify the pathogenetic and pathologic progress of AD have been done by investigators in many countries using brain tissues of people,animal models and cell models.Now in China there is no study about proteomic of AD brain of people.We carried the study in the Geronotlogical Research Center of the general hospital of PLA with the samples conserved in paraffin wax and in refrigerator at -80℃.
The study included three parts:1)we selected the samples of AD and samples of control by HE stain and immunohistochemistry stain.Combining the clinical diagnosis,we designed the two groups after we obtained the pathologic diagnosis; 2) we isolated proteins of the two groups(AD group and control group) by fluorescence two-dimensional differential gel electrophoresis(2D-DIGE).Then identified the proteins by mass spectrometry and analyzed the association between the AD pathogenesy and the proteins.3)at the end,we validated part of the altered proteins by western blotting.
The first part:pathobiology.Anti-β-Amyloid,anti-AT8,anti-Ubiquitin were used to obtain the AD samples and contol samples,which are the most common antibodies admitted by people to characterize the AD's pathological changes.We used anti-Synuclin to exclude Lewy' body dementia and Parkinson's dementia. With all these pathological changes we at length defined two groups:AD group and control group with each group including 6 cases.
The second part:proteom study.After extracted protein from the cases of two groups,we ran the 2D-DIGE.The protein spots were analyzed by softwares of Image Master 2D Platinum,Image Quant and DeCyder(Version6.5) and then were identified by mass spectrometry.After searching in IPI HUMAN(v3.23) database,we obtained 14 different proteins.The different proteins are of oxidation, energy-related enzymes,and chaperonin et al.4 of the proteins have not been reported before in the studies of other investigators.Some alteration of protein level didn't correspond with that of the previous studies.
The third part of the study was to validate the results of 2D-DIGE with western blotting.We detected the altered level of HSP90αand the two results corresponded.This demonstrated the stability and reliability of the 2D-DIGE.
This study leads a new road to ascertain the pathogenesy of AD,and to find new diagnosis and therapy methods to AD.
引文
1.贾建平主编.临床痴呆病学.北京大学医学出版社.2008,161.164
2.张振馨,刘君,洪震,等.中国北京、西安、上海和成都地区痴呆亚型患病率的研究.中国现代神经疾病杂志.2005,5(3):156-157
3.Hendrie HC.Epidemiology of Alzheimer's disease.Geriatrics.1997,52(Suppl 2):S4-8
4.Owen JB,Di Domenico F,Sultana R,et al.Proteomics-determined differences in the concanavalin-A-fractionated proteome of hippocampus and inferior parietal lobule in subjects with Alzheimer's disease and mild cognitive impairment:implications for progression of AD.J Proteome Res.2009,8(2):471-482
5.Ineichen B.The geography of dementia:an approach through epidemiology.Health Place.1998,4(4):383-394
6.Lobo A,Launer L J,Fratiglioni L,et al.Prebalence of dementia and major subtypes in Europe:a collaborative study of population-based cohorts.Neurologic diseases in the elderly research group.Neurology.2000,54(11 suppl 5):S4-9
7.Derouesne C.What is dementia? A fuzzy construct.Psychol Neuropsychiatr Vieil.2003,1(1):15-24
8.Casal C,Serratosa J,Tusell JM.Effects of beta-AP peptides on activation of the transcription factor NF-kappa B and in cell proliferation in glial cell cultures.Neurosci Res.2004,48(3):315-323
9.Wenning GK,Jellinger KA.The role of alpha-synuclein and tau in neurodegenerative movement disorders.Curr Opin Neurol.2005,18(4):357-362
10.唐湘祁,刘正清,谭利明,等.泛素在阿尔茨海默病神经原纤维缠结和老年斑中的表达.中华神经科杂志.2004,37(5):393-395
11.Tonge R,Shaw J,Middleton B,et al.Validation and development of fluorescence two-dimensional differential gel electrophoresis proteomics technology.Proteomics.2001,1(3):377-396
12.S.J.Schonberger,P.F.Edgar,R.Kydd,et al.Proteomic analysis of the brain in Alzheimer's disease:molecular phenotype of a complex disease process. Proteomics.2001,1(12):1519-1528
13.Mazzola,M.A.Sirover.Reduction of glyceraldehyde-3-phosphate dehydrogenase activity in Alzheimer's disease and in Huntington's disease fibroblasts.J Neurochem.2001,76(2):442-449
14.D.A.Butterfield,H.F.Poon,D.St Clair,et al.Redox proteomics identification of oxidatively modified hippocampal proteins in mild cognitive impairment:insights into the development of Alzheimer's disease.Neurobiol.Dis.2006,22(2):223-232
15.S.F.Newman,R.Sultana,M.Perluigi,et al.An increase in S-glutathionylated proteins in the Alzheimer's disease inferior parietal lobule,a proteomics approach.J.Neurosci.Res.2007,85(7):1506-1514
16.M.S.Parihar,GJ.Brewer.Mitoenergetic failure in Alzheimer disease.Am.J.Physiol,Cell Physiol.2007,292(1):C8-C23
17.Tanea T.Reed,William M.Pierce,William R,et al.Proteomic identification of HNE-bound proteins in early Alzheimer disease:Insights into the role of lipid peroxidation in the progression of AD.Brain Research.2009,Apr 15
18.Rukhsana Sultana,Debra Boyd-Kimball,Jain Caid,et al.Proteomics Analysis of the Alzheimer's Disease Hippocampal Proteome.Journal of Alzheimer's Disease.2007,11(2):153-164
19.W.Meier-Ruge,P.Iwangoff,K.Reichlmeier.Neurochemical enzyme changes in Alzheimer's and Pick's disease.Arch Gerontol Geriatr.1984,3(2):161-165
20.Shelley F.Newman,Rukhsana Sultana,Marzia Perluigi,et al.An increase in S-glutathionylated proteins in the Alzheimer's disease inferior parietal lobule,a proteomics approach.Journal of Neuroscience Research.2007,85(7):1506-1514
21.Francesco Paoletti,Alessandra Mocali,Marco Marchi,et al.Occurrence of transketolase abnormalities in extracts of foreskin fibroblasts from patients with Alzheimer's disease.Biochemical and Biophysical Research Communications.1990,172(2):396-401
22.Francesco Paoletti,Alessandra Mocali,Donatella Tombaccini.Cysteine Proteinases Are Responsible for Characteristic Transketolase Alterations in Alzheimer Fibroblasts.Journal of cellular physiology.1997,172(1):63—68
23.Eisinger J,Arroyo P,Braquet M,et al.Erythrocyte transketolases and Alzheimer disease.Rev Med Interne.1994,15(6):387-389
24.Butterworth RF,Besnard AM.Thiamine-dependent enzyme changes in temporal cortex of patients with Alzheimer's disease.Metab Brain Dis.1990,5(4):179-184
25.Mastrogiaeomo F,Bergeron C,Kish SJ.Brain alpha-ketoglutarate dehydrogenase complex activity in Alzheimer's disease.J Neurochem.1993,61(6):2007-2014.
26.J A.Molinal,F.J.Jiménez-Jiménez,A.Hernánz,et al.Cerebrospinal fluid levels of thiamine in patients with Alzheimer's disease.J Neural Transm.2002,109(7-8):1035-1044
27.Louvet-Vallee S.ERM proteins:from cellular architecture to cell signaling.Biol Cell.2002,92(5):305-316
28.Gautreau A,Poullet P,Louvard D,et al.Ezrin,a plasma membrane-microfilament linker,signals cell survival through the phosphatidylinositol 3-kinase/Akt pathway.Proc Natl Acad Sci USA,1999,96(13):7300-7305
29.Paglini G,Kunda P,Quiroga S,et al.Suppression of radixin and moesin alters growth cone morphology,motility,and process formation in primary cultured neurons.J Cell Biol.1998,143(2):443-455
30.林剑国,石淑仙,刘云海.Moesin分子及其特性.国外医学分子生物学分册.2001,23(3):42-45
31.Nusrat A,Parkos CA,Verkade P,et al.Tight junctions are membrane microdomains.J Cell Sci.2000,113(Pt 10):1771-1778
32.徐延豪,杜喆,石玉秀.肌动蛋白与纽蛋白在神经干细胞定向分化为神经元过程中的表达.中国组织化学与细胞化学杂志.2005,14(5):577-581
33.K.A.Frey,S.Minoshima,D.E.Kuhl.Neurochemical imaging of Alzheimer's disease and other degenerative dementias.Q J Nucl Med.1998,42(3):166-178
34.T.H.Maren.The kinetics of HCO- synthesis related to fluid secretion,pH control,and CO2 elimination.Annu Rev Physiol.1988,50:695-717
35.Constantinidis J.Alzheimer's dementia and zinc.Schweiz Arch Neurol Psychiatr.1990,141(6):523-556
36.Miao-Kun Sun,Daniel L Alkon.Carbonic anhydrase gating of attention:memory therapy and enhancement.Trends in Pharmacological Sciences.2002,23(2):83-89
37.Roman Vlkolinsky,Nigel Cairns,Michael Fountoulakis,et al.Decreased brain levels of 2',3 '-cyclic nucleotide-3'-phosphodiesterase in Down syndrome and Alzheimer's disease Neurobiology of Aging.2001,22(4):547-553
38.R Sultana,D.Boyd-Kimball,H.F.Poon,et al.Redox proteomics identification of oxidized proteins in Alzheimer's disease hippocampus and cerebellum:An ap-proach to understand pathological and biochemical alterations in AD.Neurobiol Aging.2006,27(11):1564-1576
39.W.S.Sly,P.Y.Hu.Human carbonic anhydrases and carbonic anhydrase deficiencies.Annu Rev Biochem.1995,64:375-401
40.Monica Hies,Mircea D.Banciu,Marc A.Hies,et al.Carbonic Anhydrase Activators:Design of High Affinity Isozymes I,II,and IV Activators,Incorporating Tri-/Tetrasubstituted-pyridinium-azole Moieties.J.Med.Chem.2002,45(2):504-510
41.A Scozzafava,C.T.Supuran.Carbonic anhydrase activators:high affinity isozymes I,II and IV activators,incorporating a P-alanyl-histidine scaffold.J Med Chem.2002,45(2):284-291.
42.C Temperini,A.Scozzafava,L.Puccetti,et al.Carbonic anhydrase activators:X-ray crystal structure of the adduct of human isozyme II with histidine as a platform for the design of stronger activators.Bioorg Med Chem Lett.2005,15(23):5136-5141.
43.Sun M-K,Alkon DL.Pharmacological enhancement of synaptic efficacy,spatial learning,and memory through carbonic anhydrase activation in rats.The Journal of Pharmacology and Experimental Therapeutics.2001,297(3):961-967
44.Casini A,Caccia S,Scozzafava A,et al.Carbonic anhydrase activators.The selective serotonin reuptake inhibitors fluoxetine,sertraline and citalopram are strong activators of isozymes I and II.Bioorg Med Chem Lett.2003,13(16):2765-2768
45.Song Qin,Xiang-You Hu,Hao Xu,et al.Regional alteration of synapsin I in the hippocampal formation of Alzheimer's disease patients.Acta Neuropathologica.2003,107(3):209-215
46.Perdahl E,Adolfsson R,Alafuzoff I,et al.Synapsin I(protein I)in different brain regions in senile dementia of Alzheimer type and in multi-infarct dementia.Neurology.1984,60(2):133-141
47.Hamos JE,DeGennaro LJ,Drachman DA.Synaptic loss in Alzheimer's disease and other dementias.Neurology.1989,39(3):355-361
48.K.Tsamis,D.Mytilinaios,S.N.Njau,et al.The combination of silver techniques for studying the pathology of alzheimer's disease.International Journal of Neuroscience.2008,118(2):257 -266
49.Wurtman RJ,Cansev M,Ulus IH.Synapse Formation Is Enhanced by Oral Administration of Uridine and DHA,the Circulating Precursors of Brain Phosphatides.J Nutr Health Aging.2009,13(3):189-197
50.Branks PL,Wilson MC.Patterns of gene expression in the murine brain revealed by in situ hybridization of brain-specific mRNAs.Brain Res.1986,387(1):1-16
51.Oyler GA,Higgins GA,Hart RA,et al.The identification of a novel synaptosomal-associated protein,SNAP-2 5,differentially expressed by neuronal subpopulations.J Cell Biol.1989,109(6Ptl):3039-3052
52.Geddes JW,Hess EJ,Hart RA,et al.Lesions of hippocampal circuitry define synaptosomal-associated protein-25(SNAP-25)as a novel presynaptic marker.Neuroscience.1990,38(2):515-525
53.Oyler GA,Polli JW,Higgins GA,et al.Distribution and expression of SNAP-25 immunoreactivity in rat brain,rat PC-12 cells and human SMS-KCNR neuroblastoma cells.Brain Res Dev Brain Res.1992,65(2):133-146
54.Walch-Solimena C,Blasi J,Edelmann L,et al.The t-SNAREs syntaxin 1 and SNAP-25 are present on organelles that participate in synaptic vesicle recycling.J Cell Biol.1995,128(4):637-645
55.Duc C,Catsicas S.Ultrastructural localization of SNAP-25 within the rat spinal cord and peripheral nervous system.J Comp Neurol.1995,356(1):152-163
56.Grosse G,Grosse J,Tapp R,et al.SNAP-25 requirement for dendritic growth of hippocampal neurons.J Neurosci Res.1999,56(5):539-546
57.Sollner T,Whiteheat SW,Brunner M,et al.Snap receptors implicated in vesicle targeting and fusion.Nature.1993,362:318-324
58.Low P,Norlin T,Risinger C,et al.Inhibition of neurotransmitter release in the lamprey reticulospinal synapse by antibody-mediated disruption of SNAP-25 function.Eur J Cell Biol.1999,78(11):787-793
59.Banerjee A,Kowalchyk JA,DasGupta BR,et al.SNAP-25 is required for a late postdocking step in Ca2+-dependent exocytosis.J Biol Chem.1996,271(34):20227-20230
60.Susi Greber,Gert Lubec,Nigel Cairns,et al.Decreased levels of synaptosomal associated protein 25 in the brain of patients with Down Syndrome and Alzheimer's disease.Electrophoresis.1999,20(4-5):928-934
61.Dessi F,Colle MA,Hauw JJ,et al.Accumulation of SNAP-25 immunoreactive material in axons of Alzheimer's disease.Neuroreport.1997,8(17):3685-3689
62.Karen Hoppens Gylys,Jeffrey A.Fein,Fusheng Yang,et al.Increased cholesterol in AP-positive nerve terminals from Alzheimer's disease cortex.Neurobiology of Aging.2007,28(1):8-17
63.Ferrer I,Marti E,Tortosa A,et al.Dystrophic neurites of senile plaques are defective in proteins involved in exocytosis and neurotransmission.J Neuropathol Exp Neurol.1998,57(3):218-225
64.Chun-I.Sze,Hong Bi,Bette K.Kleinschmidt-DeMasters,et al.Selective regional loss of exocytotic presynaptic vesicle proteins in Alzheimer's disease brains.Journal of the Neurological Sciences.2000,175(2):81-90
65.Shimohama S,Kamiya,Taniguchi T,et al.Differential involvement of synaptic vesicle and presynaptic plasma membrane proteins in Alzheimer's disease.Biochem Biophy Res Comm.1997,236(2):239-242
66.Lue L-F,Brachova L,Civin WH,et al.Inflammation,A[beta]deposition,and neurofibrillary tangle formation as correlates of Alzheimer's disease neurodegeneration.J Neuropathol Exp Neurol.1996,55(10):1083-1088
67.Lue L-F,Kuo Y-M,Roher AE,et al.Soluble amyloid[beta]peptide concentration as a predictor of synaptic change in Alzheimer's disease.Am J Pathol.1999,155(3):853-862
68.Minger Stephen L,Honer William G,Esiri margaret M,et al.Synaptic Pathology in Prefrontal Cortex is Present Only with Severe Dementia in Alzheimer Disease.Journal of neuropathology and experimental neurology.2001,60(10):929-936
69.Elizabeta B.Mukaetova-Ladinska,Francisco Garcia-Siera,Jenny Hurt,et al.Staging of Cytoskeletal and β-Amyloid Changes in Human Isocortex Reveals Biphasic Synaptic Protein Response during Progression of Alzheimer's Disease.American Journal of Pathology.2000,157(2):623-636
70.Clinton J,Blackman SE,Royston MC,et al.Differential synaptic loss in the cortex in Alzheimer's disease:a study using archival material.Neuroreport.1994,5(4):497-500
71.M Colombini.VDAC:the channel at the interface between mitochondria and the cytosol.Mol.Cell.Biochem.2004,256-257(1-2):107-115
72.Bradford BU,Rusyn I.Swift increase in alcohol metabolism(SIAM):understanding the phenomenon of hypermetabolism in liver.Alcohol.2005,35(1):13-17
73.Wallace DC.Mitochondrial diseases in man and mouse.Science.1999,283(5407):1482-1488
74.Gincel D,Zaid H,Shoshan-Barmatz V.Calcium binding and translocation by the voltage-dependent anion channel:a possible regulatory mechanism in mitochondrial function.Biochem J.2001,358(Ptl):147-155
75.McCallum CD,Do H,Johnson AE,et al .The interaction of the chaperonin tailless complex polypeptide 1(TCP1)Ring Complex(TRiC)with ribosome-bound nascent chains examined using photo-cross-linking.The Journal of Cell Biology.2000,149(3):591-601
76.Kubota H.Function and regulation of cytosolic molecular chaperone CCT.Vitam Horm.2002,65:313-331
77.Bourke GJ,EIAlami W,Wilson SJ,et al.Slow axonal transport of the cytosolic chaperonin CCT with Hsc73 and actin in motor neurons.J Neurosci Res.2002,68(1):292-235
78.Kubo to H,Hynes G,Carne A,et al.Identification of Tcp-1-related genes encoding divergent subunits of the TCP-1-containing chaperonin.Curr Biol. 1994,4(2):89
79.Gething MJ,Sambrook J.Protein folding and chaperonins.Nature.1992,355(b355):33-45
80.Byong Chul Yoo,Seong Hwan Kim,Nigel Cairns,et al.Deranged Expression of Molecular Chaperones in Brains of Patients with Alzheimer's Disease.Biochemical and Biophysical Research Communications.2001,280(1):249-258
81.Elisabeth Schuller,Talin Gulesserian,Rainer Seidl,et al.Brain t-complex polypeptide 1(TCP-1)related to its natural substrate β1 tubulin is decreased in Alzheimer's disease.Life Sciences.2001,69(3):263-270
82.Soo ET,Ng YK,Bay BH,et al.Heat shock proteins and neurodegenerative disorders.Scientific World Journal.2008,8:270-274
83.Young JC,Moarefi I,Hartl FU.Hsp90:a specialized but essential protein -folding tool.J Cell Biol.2001,154(2):267-273
84.Hickey E,Brandon SE,Smale G,et al.Sequence and regulation of a gene encoding a human 892kilodalton heat shock protein.Mol Cell Biol.1989,26(9):15-21.
85.Maloney A,Workman P.Hsp90 as a new therapeutic target for cancer therapy:the story unfolds.Expert Opin Biol Ther.2002,2(1):3-24
86.Malaitsev VV,Bogdanova IM,Makarova OV.Heat shock proteins and their role in the development of pathological processes.Arkh Patol.2008,70(6):31-38
87.Young JC,Moarefi I,Hartl FU.Hsp90:a specialized but essential protein-folding tool.J Cell Biol.2001,154(2):267-273
88.Panaretou B,Prodromou C,Roe SM,et al.ATP binding and hydrolysis are essential to the function of the Hsp90 molecular chaper one in vivo.EMBO J.1998,17(16):4829-4836
89.PrattWB,Toft DO.Regulation of signaling p rotein function andtrafficking by the hsp90 /hsp70 -based chaperone machinery.Exp BiolMed(Maywood).2003,228(2):111 -133
90.Hurtado-Lorenzo A,Anand VS.Heat Shock Protein 90 Modulates LRRK2 Stability:Potential Implications for Parkinson's Disease Treatment.The Journal of Neuroscience.2008,28(27):6757-6759
91.Zhang H,WuW,Du Y,et al.Hsp90/p50cdc37 is required formixed - lineage kinase(MLK) 3 signaling.J Biol Chem.2004,279(19):19457-19463
92.Christopher G.Evans,Susanne Wise" n,Jason E.Gestwickil.Heat Shock Proteins 70 and 90 Inhibit Early Stages of Amyloid-(1-42) Aggregation in Vitro.The journal of biological chemistry.2006,281(44):33182-33191
93.Taldone T,Sun W,Chiosis G.Discovery and development of heat shock protein 90 inhibitors.Bioorg Med Chem.2009,17(6):2225-2235
94.胡鹤本,朱人敏,吴波,等.热休克蛋白90alpha在胃癌中的表达及其意义.中华消化内镜杂志.2005,22(1):52-53
95.Luisa Benussil,Roberta Ghidonil,Anna Paterlini,et al.Interaction between tau and alpha-synuclein proteins is impaired in the presence of P301L tau mutation.Experimental Cell Research.2005,308:78-84
96.Dou F,Netzer W J,Tanemura K,et al.Chaperones increase association of tau protein with microtubules.Proc Natl Acad Sci USA.2003,100(2):721-726
97.Powers MV,Workman P.Targeting of multiple signalling pathways by heat shock protein 90 molecular chaperone inhibitors.Endocr Relat Cancer.2006,13Suppl1:S125-S135
98.Wenjie Luol,Anna Rodina,Gabriela Chiosis.Heat shock protein 90:translation from cancer to Alzheimer's disease treatment?.BMC Neuroscience.2008,9(Suppl 2):S7
99.Chad A.Dickey,Adeela Kamal,Karen Lundgren,et al.The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteins.The Journal of Clinical Investigation.2007,117(3):648-658
100.Chad A.Dickey,John Koren,Yong-Jie Zhang,et al.Akt and CHIP coregulate tau degradation through coordinated interactions.PNAS.2008,105(9):3622-3627
101.T.Yokota,M.Mishra,H.Akatsu,et al.Brain site-specific gene expression analysis in Alzheimer's disease patients.European Journal of Clinical Investigation.2006,36(11):820-830
102.Elena Tortosa,Ismael Santa-Mafia,Francisco Moreno,et al.Binding of Hsp90 to Tau Promotes a Conformational Change and Aggregation of Tau Protein.Journal of Alzheimer's Disease.2009,Mar6
103.Shawn G.Anthonya,Hyman M.Schipperb,Rosemarie Tavaresa,et al.Stress protein expression in the Alzheimer-diseased choroid plexus.Journal of Alzheimer's Disease.2003,5(3):171-177
104.Conrad Johanson,Paul McMillan,Rosemarie Tavares,et al.Homeostatic capabilities of the choroid plexus epithelium in Alzheimer's disease.Cerebrospinal Fluid Res.2004,1(1):3
105.胡明均,刘勇,王家宁,等.热休克蛋白90alpha在血管内皮生长因子165基因治疗大鼠脑梗死中的表达及意义.上海医学.2005,28(3):233-235
106.C D Smith,J M Carney,P E Starke-Reed,et al.Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease.Proc Natl Acad Sci U S A.1991,88(23):10540-10543
107.Cooper A,Vergara F,Duffy T.Cerebral glutamine synthetase.In:Hertz L,Kvamme E,McGeer E,Schousboe A,eds.Glutamine,Glutamate,and GABA in the Central Nervous System.New York,NY:Alan R Liss Inc;1983:77-93
108.Kish S,Chang L,Dixon L,et al.Cerebellar glutamate metabolizing enzymes in spinocerebellar ataxia type I.Metab Brain Dis.1994,9(2):97-103
109.Lavoie J,Giguere J,Layrargues G,et al.Activities of neuronal and astrocytic marker enzymes in autopsied brain tissue from patients with hepatic encephalopathy.Metab Brain Dis.1987,2(4):283-290
110.LePrince G,Delaere P,Fages C,et al.Glutamine synthetase(GS) expression is reduced in senile dementia of the Alzheimer type.Neurochem Res.1995,20(7):859-862
111.Smith CD,Carney JM,Starke-Reed PE,et al.Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease.Proc Natl Acad Sci U S A.1991,88(23):10540-10543
112.Stephen R.Robinson.Changes in the cellular distribution of glutamine synthetase in Alzheimer's disease.Journal of Neuroscience Research.2001,66(5):972-980
113.D.Allan Butterfield,Kenneth Hensley,Ramela Cole,et al.Oxidatively Induced Structural Alteration of Glutamine Synthetase Assessed by Analysis of Spin Label Incorporation Kinetics:Relevance to Alzheimer's Disease.Journal of Neurochemistry.1997,68(6):2451-2457
114.Jorgensen OS,Brooksbank BW,Balázs R.Neuronal plasticity and astrocytic reaction in Down syndrome and Alzheimer disease.J Neurol Sci.1990,98(1):63-79
115.Markesbery WR,Carney JM.Oxidative alterations in Alzheimer's disease.Brain Pathol.1999,9(1):133-146
116.Burbaeva GSh,Boksha IS,Turishcheva MS,et al.Impaired cerebral glutamate metabolism in mental diseases(Alzheimer's disease,schizophrenia).Vestn Ross Akad Med Nauk.2001,(7):34-37
117.Butterfield DA.Amyloid beta-peptide(1-42)-induced oxidative stress and neurotoxicity:implications for neurodegeneration in Alzheimer's disease brain.A review.Free Radic Res.2002,36(12):1307-1313
118.Gulnur Sh.Burbaeva,Irina S.Boksha,Elena B.Tereshkina,et al.Glutamate Metabolizing Enzymes in Prefrontal Cortex of Alzheimer's Disease Patients.Neurochemical Research.2005,30(11):1443-1451
119.Stephen R.Robinson.Neuronal expression of glutamine synthetase in Alzheimer's disease indicates a profound impairment of metabolic interactions with astrocytes.Neurochemistry International.2000,36(4-5):471-482
120.Alessandra Castegna,Michael Aksenov,Marina Aksenova,et al.Proteomic identification of oxidatively modified proteins in alzheimer's disease brain.part Ⅰ:creatine kinase BB,glutamine synthase,and ubiquitin carboxy-terminal hydrolase L-1.Free Radical Biology and Medicine.2002,33(4):562-571
121.Hensley K,Hall N,Subramaniam R,et al.Brain Regional Correspondence Between Alzheimer's Disease Histopathology and Biomarkers of Protein Oxidation.J.Neurochem.1995,65(5):2146-2156
122.Hayrettin Tumani,GuoQiu Shen,James B.Peter,et al.Glutamine Synthetase in Cerebrospinal Fluid,Serum,and Brain A Diagnostic Marker for Alzheimer Disease?.Arch Neurol.1999,56(10):1241-1246
123.谢作斌,王友群.ERp29-一种新的内质网蛋白.医学综述.2009,15(3):374-377
124.HubbardMJ,Mangum JE,McHugh NJ.Purification and biochemical characterization of native ERp29 from rat liver.Biochem J.2004,383(Pt3):589-597
125.Matus S.The stress rheostat:an interp lay between the unfolded protein response(UPR)and autophagy in neurodegeneration.Curr MolMed.2008,8(3):157-172
126.Mkrtchian S,Sandalova T.ERp29,an unusual redox2inactive member of the thioredoxin family.Antioxid Redox Signal.2006,8(3-4):325-337
127.Laskey RA.Nucleosomes are assembled by an acidic p rotein which binds histones and transfers them to DNA.Nature.1978,275(5679):416-420
128.llis RJ.Molecular chaperones:assisting assembly in addition to folding.Trends Biochem Sci.2006,31(7):395-401
129.Pagani M.Endop lasmic reticulum oxidoreductin 121beta(ER012Lbeta),a human gene induced in the course of the unfolded protein response.J Biol Chem.2000,275(31):23685-23692
130.Sitia R,Braakman I.Quality control in the endop lasmic reticulump rotein factory.Nature.2003,426(6968):891-894
131.Herrmann JM,Malkus P,Schekman R.Out of the ER22outfitters,escorts and guides.Trends Cell Biol.1999,9(1):527
132.Hughes GJ,Frutiger S.Human liver p rotein map:update 1993.Electrophoresis.1993,14(11):1216-1222.
133.Bendheim PE,Bolton DC.A 54-kDa normal cellular protein may be the precursor of the scrapie agent protease-resistant protein.Proc Natl Acad Sci USA.1986,83(7):2214-2218
[1]陈主初,肖志强.疾病蛋白质组学[M].北京:化学工业出版社.2006.1-106
[2]Wasinger VC,Cordwell S J,Cerpa-Poljak A,et al.Progress with gene product mapping of the molicutes:Mycoplasma genitalium[J].Electrophoresis.1995,16(7):1090-1094
[3]钱小红,贺福初.蛋白质组学:理论与方法[M].北京:科学出版社. 2003.12-95
[4]Kim SI,Voshol H,van Oostrum J,et al.Neuroproteomics:expression profiling of the brain's proteomes in health and disease[J].Neurochem Res.2004,29(6):1317-1331
[5]Schonberger SJ,Edgar PF,Kydd R,et al.Proteomic analysis of the brain in Alzheimer's disease:Molecular phenotype of a complex disease process[J].Proteomics.2001,1(12):1519-1528
[6]Langen H,Berndt P,Roder D,et al.Two-dimensional map of human brain proteins[J].Electrophoresis.1999,20(4-5):907-916
[7]Yoo BC,Kim SH,Cairns N,et al.Deranged expression of molecular chaperones in brains of patients with Alzheimer's disease[J].Bilchemical and Biophysical Research Communications.2001,280(l):249-258
[8]Aksenov MY,Aksenova MV,Butterfield DA,et al.Protein oxidation in the brain in Alzheimer's disease[J].Neuroscience.2001,103(2):373-383
[9]Pamplona R,Dalfo E,Ayala V,et al.Proteins in human brain cortex are modified by oxidation,glycoxidation,and lipoxidation.Effects of Alzheimer disease and identification of lipoxidation targets[J].The Journal of Biological Chemistry.2005,280(22):21522-21530
[10]Korolainen MA,Goldsteins G,Nyman TA,et al.Oxidative modification of proteins in the frontal cortex of Alzheimer's disease brain[J].Neurobiology of Aging.2006,27(1):42-53
[1 l]Woltjer RL,Cimino PJ,Boutte AM,et al.Proteomic determination of widespread detergent-insolubility including Abeta but not tau early in the pathogenesis of Alzheimer's disease[J].FASEB J.2005,19(13):1923-1925
[12]Sultana R,Boyd-Kimball D,Poon HF,et al.Redox proteomics identification of oxidized proteins in Alzheimer's disease hippocampus and cerebellum:An approach to understand pathological and biochemical alterations in AD[J].Neurobiology of Aging.2006,27(11):1564-1576
[13]Porchet R,Probst A,Bouras C,et al.Analysis of glial acidic fibrillary protein in the human entorhinal cortex during aging and in Alzheimer's disease[J].Proteomics.2003,3(8):1476-1485
[14]Korolainen MA,Auriola S,Nyman TA,et al.Proteomic analysis of glial fibrillary acidic protein in Alzheimer's disease and aging brain[J]. Neurobiology of Disease.2005,20(3):858-870
[15]Wang Q,Woltjer RL,Cimino PJ,et al.Proteomic analysis of neurofibrillary tangles in Alzheimer disease identifies GAPDH as a detergent-insoluble paired helical filament tau binding protein[J].FASEB J.2005,19(7):869-871
[16]Cottrell BA,Gal van V,Banwait S,et al.A pilot proteomic study of amyloid precursor interactors in Alzheimer's disease[J].Ann Neurol.2005,58(2):277-289
[17]Sultana R,Boyd-Kimball D,Poon HF,et al.Oxidative modification and down-regulation of Pinl in Alzheimer's disease hippocampus A redox proteomics analysis[J].Neurobiology of Aging.2006,27(7):918-925
[18]Choi J,Levey AI,Weintraub ST,et al.Oxidative modifications and down-regulation of ubiquitin carboxyl-terminal hydrolase LI associated with idiopathic Parkinson's and Alzheimer's diseases[J].The Journal of Biological Chemistry.2004,279(13):13256-13264
[19]Choi J,Rees HD,Weintraub ST,et al.Oxidative modifications and aggregation of Cu,Zn-superoxide dismutase associated with Alzheimer and Parkinson diseases[J].The Journal of Biological Chemistry.2005,280(12):11648-11655
[20]Choi J,Sullards MC,Olzmann J A,et al.Oxidative damage of DJ-1 is linked to sporadic Parkinson and Alzheimer diseases[J].The Journal of Biological Chemistry.2006,281(16):10816-10824
[21]Ho L,Sharma N,Blackman L,et al.From poteomics to biomarker discovery in Alzheimer's disease[J].Brain Research Reviews.2005,48(2):360-369
2.张振馨,刘君,洪震,等.中国北京、西安、上海和成都地区痴呆亚型患病率的研究.中国现代神经疾病杂志.2005,5(3):156-157
3.Hendrie HC.Epidemiology of Alzheimer's disease.Geriatrics.1997,52(Suppl 2):S4-8
4.Owen JB,Di Domenico F,Sultana R,et al.Proteomics-determined differences in the concanavalin-A-fractionated proteome of hippocampus and inferior parietal lobule in subjects with Alzheimer's disease and mild cognitive impairment:implications for progression of AD.J Proteome Res.2009,8(2):471-482
5.Ineichen B.The geography of dementia:an approach through epidemiology.Health Place.1998,4(4):383-394
6.Lobo A,Launer L J,Fratiglioni L,et al.Prebalence of dementia and major subtypes in Europe:a collaborative study of population-based cohorts.Neurologic diseases in the elderly research group.Neurology.2000,54(11 suppl 5):S4-9
7.Derouesne C.What is dementia? A fuzzy construct.Psychol Neuropsychiatr Vieil.2003,1(1):15-24
8.Casal C,Serratosa J,Tusell JM.Effects of beta-AP peptides on activation of the transcription factor NF-kappa B and in cell proliferation in glial cell cultures.Neurosci Res.2004,48(3):315-323
9.Wenning GK,Jellinger KA.The role of alpha-synuclein and tau in neurodegenerative movement disorders.Curr Opin Neurol.2005,18(4):357-362
10.唐湘祁,刘正清,谭利明,等.泛素在阿尔茨海默病神经原纤维缠结和老年斑中的表达.中华神经科杂志.2004,37(5):393-395
11.Tonge R,Shaw J,Middleton B,et al.Validation and development of fluorescence two-dimensional differential gel electrophoresis proteomics technology.Proteomics.2001,1(3):377-396
12.S.J.Schonberger,P.F.Edgar,R.Kydd,et al.Proteomic analysis of the brain in Alzheimer's disease:molecular phenotype of a complex disease process. Proteomics.2001,1(12):1519-1528
13.Mazzola,M.A.Sirover.Reduction of glyceraldehyde-3-phosphate dehydrogenase activity in Alzheimer's disease and in Huntington's disease fibroblasts.J Neurochem.2001,76(2):442-449
14.D.A.Butterfield,H.F.Poon,D.St Clair,et al.Redox proteomics identification of oxidatively modified hippocampal proteins in mild cognitive impairment:insights into the development of Alzheimer's disease.Neurobiol.Dis.2006,22(2):223-232
15.S.F.Newman,R.Sultana,M.Perluigi,et al.An increase in S-glutathionylated proteins in the Alzheimer's disease inferior parietal lobule,a proteomics approach.J.Neurosci.Res.2007,85(7):1506-1514
16.M.S.Parihar,GJ.Brewer.Mitoenergetic failure in Alzheimer disease.Am.J.Physiol,Cell Physiol.2007,292(1):C8-C23
17.Tanea T.Reed,William M.Pierce,William R,et al.Proteomic identification of HNE-bound proteins in early Alzheimer disease:Insights into the role of lipid peroxidation in the progression of AD.Brain Research.2009,Apr 15
18.Rukhsana Sultana,Debra Boyd-Kimball,Jain Caid,et al.Proteomics Analysis of the Alzheimer's Disease Hippocampal Proteome.Journal of Alzheimer's Disease.2007,11(2):153-164
19.W.Meier-Ruge,P.Iwangoff,K.Reichlmeier.Neurochemical enzyme changes in Alzheimer's and Pick's disease.Arch Gerontol Geriatr.1984,3(2):161-165
20.Shelley F.Newman,Rukhsana Sultana,Marzia Perluigi,et al.An increase in S-glutathionylated proteins in the Alzheimer's disease inferior parietal lobule,a proteomics approach.Journal of Neuroscience Research.2007,85(7):1506-1514
21.Francesco Paoletti,Alessandra Mocali,Marco Marchi,et al.Occurrence of transketolase abnormalities in extracts of foreskin fibroblasts from patients with Alzheimer's disease.Biochemical and Biophysical Research Communications.1990,172(2):396-401
22.Francesco Paoletti,Alessandra Mocali,Donatella Tombaccini.Cysteine Proteinases Are Responsible for Characteristic Transketolase Alterations in Alzheimer Fibroblasts.Journal of cellular physiology.1997,172(1):63—68
23.Eisinger J,Arroyo P,Braquet M,et al.Erythrocyte transketolases and Alzheimer disease.Rev Med Interne.1994,15(6):387-389
24.Butterworth RF,Besnard AM.Thiamine-dependent enzyme changes in temporal cortex of patients with Alzheimer's disease.Metab Brain Dis.1990,5(4):179-184
25.Mastrogiaeomo F,Bergeron C,Kish SJ.Brain alpha-ketoglutarate dehydrogenase complex activity in Alzheimer's disease.J Neurochem.1993,61(6):2007-2014.
26.J A.Molinal,F.J.Jiménez-Jiménez,A.Hernánz,et al.Cerebrospinal fluid levels of thiamine in patients with Alzheimer's disease.J Neural Transm.2002,109(7-8):1035-1044
27.Louvet-Vallee S.ERM proteins:from cellular architecture to cell signaling.Biol Cell.2002,92(5):305-316
28.Gautreau A,Poullet P,Louvard D,et al.Ezrin,a plasma membrane-microfilament linker,signals cell survival through the phosphatidylinositol 3-kinase/Akt pathway.Proc Natl Acad Sci USA,1999,96(13):7300-7305
29.Paglini G,Kunda P,Quiroga S,et al.Suppression of radixin and moesin alters growth cone morphology,motility,and process formation in primary cultured neurons.J Cell Biol.1998,143(2):443-455
30.林剑国,石淑仙,刘云海.Moesin分子及其特性.国外医学分子生物学分册.2001,23(3):42-45
31.Nusrat A,Parkos CA,Verkade P,et al.Tight junctions are membrane microdomains.J Cell Sci.2000,113(Pt 10):1771-1778
32.徐延豪,杜喆,石玉秀.肌动蛋白与纽蛋白在神经干细胞定向分化为神经元过程中的表达.中国组织化学与细胞化学杂志.2005,14(5):577-581
33.K.A.Frey,S.Minoshima,D.E.Kuhl.Neurochemical imaging of Alzheimer's disease and other degenerative dementias.Q J Nucl Med.1998,42(3):166-178
34.T.H.Maren.The kinetics of HCO- synthesis related to fluid secretion,pH control,and CO2 elimination.Annu Rev Physiol.1988,50:695-717
35.Constantinidis J.Alzheimer's dementia and zinc.Schweiz Arch Neurol Psychiatr.1990,141(6):523-556
36.Miao-Kun Sun,Daniel L Alkon.Carbonic anhydrase gating of attention:memory therapy and enhancement.Trends in Pharmacological Sciences.2002,23(2):83-89
37.Roman Vlkolinsky,Nigel Cairns,Michael Fountoulakis,et al.Decreased brain levels of 2',3 '-cyclic nucleotide-3'-phosphodiesterase in Down syndrome and Alzheimer's disease Neurobiology of Aging.2001,22(4):547-553
38.R Sultana,D.Boyd-Kimball,H.F.Poon,et al.Redox proteomics identification of oxidized proteins in Alzheimer's disease hippocampus and cerebellum:An ap-proach to understand pathological and biochemical alterations in AD.Neurobiol Aging.2006,27(11):1564-1576
39.W.S.Sly,P.Y.Hu.Human carbonic anhydrases and carbonic anhydrase deficiencies.Annu Rev Biochem.1995,64:375-401
40.Monica Hies,Mircea D.Banciu,Marc A.Hies,et al.Carbonic Anhydrase Activators:Design of High Affinity Isozymes I,II,and IV Activators,Incorporating Tri-/Tetrasubstituted-pyridinium-azole Moieties.J.Med.Chem.2002,45(2):504-510
41.A Scozzafava,C.T.Supuran.Carbonic anhydrase activators:high affinity isozymes I,II and IV activators,incorporating a P-alanyl-histidine scaffold.J Med Chem.2002,45(2):284-291.
42.C Temperini,A.Scozzafava,L.Puccetti,et al.Carbonic anhydrase activators:X-ray crystal structure of the adduct of human isozyme II with histidine as a platform for the design of stronger activators.Bioorg Med Chem Lett.2005,15(23):5136-5141.
43.Sun M-K,Alkon DL.Pharmacological enhancement of synaptic efficacy,spatial learning,and memory through carbonic anhydrase activation in rats.The Journal of Pharmacology and Experimental Therapeutics.2001,297(3):961-967
44.Casini A,Caccia S,Scozzafava A,et al.Carbonic anhydrase activators.The selective serotonin reuptake inhibitors fluoxetine,sertraline and citalopram are strong activators of isozymes I and II.Bioorg Med Chem Lett.2003,13(16):2765-2768
45.Song Qin,Xiang-You Hu,Hao Xu,et al.Regional alteration of synapsin I in the hippocampal formation of Alzheimer's disease patients.Acta Neuropathologica.2003,107(3):209-215
46.Perdahl E,Adolfsson R,Alafuzoff I,et al.Synapsin I(protein I)in different brain regions in senile dementia of Alzheimer type and in multi-infarct dementia.Neurology.1984,60(2):133-141
47.Hamos JE,DeGennaro LJ,Drachman DA.Synaptic loss in Alzheimer's disease and other dementias.Neurology.1989,39(3):355-361
48.K.Tsamis,D.Mytilinaios,S.N.Njau,et al.The combination of silver techniques for studying the pathology of alzheimer's disease.International Journal of Neuroscience.2008,118(2):257 -266
49.Wurtman RJ,Cansev M,Ulus IH.Synapse Formation Is Enhanced by Oral Administration of Uridine and DHA,the Circulating Precursors of Brain Phosphatides.J Nutr Health Aging.2009,13(3):189-197
50.Branks PL,Wilson MC.Patterns of gene expression in the murine brain revealed by in situ hybridization of brain-specific mRNAs.Brain Res.1986,387(1):1-16
51.Oyler GA,Higgins GA,Hart RA,et al.The identification of a novel synaptosomal-associated protein,SNAP-2 5,differentially expressed by neuronal subpopulations.J Cell Biol.1989,109(6Ptl):3039-3052
52.Geddes JW,Hess EJ,Hart RA,et al.Lesions of hippocampal circuitry define synaptosomal-associated protein-25(SNAP-25)as a novel presynaptic marker.Neuroscience.1990,38(2):515-525
53.Oyler GA,Polli JW,Higgins GA,et al.Distribution and expression of SNAP-25 immunoreactivity in rat brain,rat PC-12 cells and human SMS-KCNR neuroblastoma cells.Brain Res Dev Brain Res.1992,65(2):133-146
54.Walch-Solimena C,Blasi J,Edelmann L,et al.The t-SNAREs syntaxin 1 and SNAP-25 are present on organelles that participate in synaptic vesicle recycling.J Cell Biol.1995,128(4):637-645
55.Duc C,Catsicas S.Ultrastructural localization of SNAP-25 within the rat spinal cord and peripheral nervous system.J Comp Neurol.1995,356(1):152-163
56.Grosse G,Grosse J,Tapp R,et al.SNAP-25 requirement for dendritic growth of hippocampal neurons.J Neurosci Res.1999,56(5):539-546
57.Sollner T,Whiteheat SW,Brunner M,et al.Snap receptors implicated in vesicle targeting and fusion.Nature.1993,362:318-324
58.Low P,Norlin T,Risinger C,et al.Inhibition of neurotransmitter release in the lamprey reticulospinal synapse by antibody-mediated disruption of SNAP-25 function.Eur J Cell Biol.1999,78(11):787-793
59.Banerjee A,Kowalchyk JA,DasGupta BR,et al.SNAP-25 is required for a late postdocking step in Ca2+-dependent exocytosis.J Biol Chem.1996,271(34):20227-20230
60.Susi Greber,Gert Lubec,Nigel Cairns,et al.Decreased levels of synaptosomal associated protein 25 in the brain of patients with Down Syndrome and Alzheimer's disease.Electrophoresis.1999,20(4-5):928-934
61.Dessi F,Colle MA,Hauw JJ,et al.Accumulation of SNAP-25 immunoreactive material in axons of Alzheimer's disease.Neuroreport.1997,8(17):3685-3689
62.Karen Hoppens Gylys,Jeffrey A.Fein,Fusheng Yang,et al.Increased cholesterol in AP-positive nerve terminals from Alzheimer's disease cortex.Neurobiology of Aging.2007,28(1):8-17
63.Ferrer I,Marti E,Tortosa A,et al.Dystrophic neurites of senile plaques are defective in proteins involved in exocytosis and neurotransmission.J Neuropathol Exp Neurol.1998,57(3):218-225
64.Chun-I.Sze,Hong Bi,Bette K.Kleinschmidt-DeMasters,et al.Selective regional loss of exocytotic presynaptic vesicle proteins in Alzheimer's disease brains.Journal of the Neurological Sciences.2000,175(2):81-90
65.Shimohama S,Kamiya,Taniguchi T,et al.Differential involvement of synaptic vesicle and presynaptic plasma membrane proteins in Alzheimer's disease.Biochem Biophy Res Comm.1997,236(2):239-242
66.Lue L-F,Brachova L,Civin WH,et al.Inflammation,A[beta]deposition,and neurofibrillary tangle formation as correlates of Alzheimer's disease neurodegeneration.J Neuropathol Exp Neurol.1996,55(10):1083-1088
67.Lue L-F,Kuo Y-M,Roher AE,et al.Soluble amyloid[beta]peptide concentration as a predictor of synaptic change in Alzheimer's disease.Am J Pathol.1999,155(3):853-862
68.Minger Stephen L,Honer William G,Esiri margaret M,et al.Synaptic Pathology in Prefrontal Cortex is Present Only with Severe Dementia in Alzheimer Disease.Journal of neuropathology and experimental neurology.2001,60(10):929-936
69.Elizabeta B.Mukaetova-Ladinska,Francisco Garcia-Siera,Jenny Hurt,et al.Staging of Cytoskeletal and β-Amyloid Changes in Human Isocortex Reveals Biphasic Synaptic Protein Response during Progression of Alzheimer's Disease.American Journal of Pathology.2000,157(2):623-636
70.Clinton J,Blackman SE,Royston MC,et al.Differential synaptic loss in the cortex in Alzheimer's disease:a study using archival material.Neuroreport.1994,5(4):497-500
71.M Colombini.VDAC:the channel at the interface between mitochondria and the cytosol.Mol.Cell.Biochem.2004,256-257(1-2):107-115
72.Bradford BU,Rusyn I.Swift increase in alcohol metabolism(SIAM):understanding the phenomenon of hypermetabolism in liver.Alcohol.2005,35(1):13-17
73.Wallace DC.Mitochondrial diseases in man and mouse.Science.1999,283(5407):1482-1488
74.Gincel D,Zaid H,Shoshan-Barmatz V.Calcium binding and translocation by the voltage-dependent anion channel:a possible regulatory mechanism in mitochondrial function.Biochem J.2001,358(Ptl):147-155
75.McCallum CD,Do H,Johnson AE,et al .The interaction of the chaperonin tailless complex polypeptide 1(TCP1)Ring Complex(TRiC)with ribosome-bound nascent chains examined using photo-cross-linking.The Journal of Cell Biology.2000,149(3):591-601
76.Kubota H.Function and regulation of cytosolic molecular chaperone CCT.Vitam Horm.2002,65:313-331
77.Bourke GJ,EIAlami W,Wilson SJ,et al.Slow axonal transport of the cytosolic chaperonin CCT with Hsc73 and actin in motor neurons.J Neurosci Res.2002,68(1):292-235
78.Kubo to H,Hynes G,Carne A,et al.Identification of Tcp-1-related genes encoding divergent subunits of the TCP-1-containing chaperonin.Curr Biol. 1994,4(2):89
79.Gething MJ,Sambrook J.Protein folding and chaperonins.Nature.1992,355(b355):33-45
80.Byong Chul Yoo,Seong Hwan Kim,Nigel Cairns,et al.Deranged Expression of Molecular Chaperones in Brains of Patients with Alzheimer's Disease.Biochemical and Biophysical Research Communications.2001,280(1):249-258
81.Elisabeth Schuller,Talin Gulesserian,Rainer Seidl,et al.Brain t-complex polypeptide 1(TCP-1)related to its natural substrate β1 tubulin is decreased in Alzheimer's disease.Life Sciences.2001,69(3):263-270
82.Soo ET,Ng YK,Bay BH,et al.Heat shock proteins and neurodegenerative disorders.Scientific World Journal.2008,8:270-274
83.Young JC,Moarefi I,Hartl FU.Hsp90:a specialized but essential protein -folding tool.J Cell Biol.2001,154(2):267-273
84.Hickey E,Brandon SE,Smale G,et al.Sequence and regulation of a gene encoding a human 892kilodalton heat shock protein.Mol Cell Biol.1989,26(9):15-21.
85.Maloney A,Workman P.Hsp90 as a new therapeutic target for cancer therapy:the story unfolds.Expert Opin Biol Ther.2002,2(1):3-24
86.Malaitsev VV,Bogdanova IM,Makarova OV.Heat shock proteins and their role in the development of pathological processes.Arkh Patol.2008,70(6):31-38
87.Young JC,Moarefi I,Hartl FU.Hsp90:a specialized but essential protein-folding tool.J Cell Biol.2001,154(2):267-273
88.Panaretou B,Prodromou C,Roe SM,et al.ATP binding and hydrolysis are essential to the function of the Hsp90 molecular chaper one in vivo.EMBO J.1998,17(16):4829-4836
89.PrattWB,Toft DO.Regulation of signaling p rotein function andtrafficking by the hsp90 /hsp70 -based chaperone machinery.Exp BiolMed(Maywood).2003,228(2):111 -133
90.Hurtado-Lorenzo A,Anand VS.Heat Shock Protein 90 Modulates LRRK2 Stability:Potential Implications for Parkinson's Disease Treatment.The Journal of Neuroscience.2008,28(27):6757-6759
91.Zhang H,WuW,Du Y,et al.Hsp90/p50cdc37 is required formixed - lineage kinase(MLK) 3 signaling.J Biol Chem.2004,279(19):19457-19463
92.Christopher G.Evans,Susanne Wise" n,Jason E.Gestwickil.Heat Shock Proteins 70 and 90 Inhibit Early Stages of Amyloid-(1-42) Aggregation in Vitro.The journal of biological chemistry.2006,281(44):33182-33191
93.Taldone T,Sun W,Chiosis G.Discovery and development of heat shock protein 90 inhibitors.Bioorg Med Chem.2009,17(6):2225-2235
94.胡鹤本,朱人敏,吴波,等.热休克蛋白90alpha在胃癌中的表达及其意义.中华消化内镜杂志.2005,22(1):52-53
95.Luisa Benussil,Roberta Ghidonil,Anna Paterlini,et al.Interaction between tau and alpha-synuclein proteins is impaired in the presence of P301L tau mutation.Experimental Cell Research.2005,308:78-84
96.Dou F,Netzer W J,Tanemura K,et al.Chaperones increase association of tau protein with microtubules.Proc Natl Acad Sci USA.2003,100(2):721-726
97.Powers MV,Workman P.Targeting of multiple signalling pathways by heat shock protein 90 molecular chaperone inhibitors.Endocr Relat Cancer.2006,13Suppl1:S125-S135
98.Wenjie Luol,Anna Rodina,Gabriela Chiosis.Heat shock protein 90:translation from cancer to Alzheimer's disease treatment?.BMC Neuroscience.2008,9(Suppl 2):S7
99.Chad A.Dickey,Adeela Kamal,Karen Lundgren,et al.The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteins.The Journal of Clinical Investigation.2007,117(3):648-658
100.Chad A.Dickey,John Koren,Yong-Jie Zhang,et al.Akt and CHIP coregulate tau degradation through coordinated interactions.PNAS.2008,105(9):3622-3627
101.T.Yokota,M.Mishra,H.Akatsu,et al.Brain site-specific gene expression analysis in Alzheimer's disease patients.European Journal of Clinical Investigation.2006,36(11):820-830
102.Elena Tortosa,Ismael Santa-Mafia,Francisco Moreno,et al.Binding of Hsp90 to Tau Promotes a Conformational Change and Aggregation of Tau Protein.Journal of Alzheimer's Disease.2009,Mar6
103.Shawn G.Anthonya,Hyman M.Schipperb,Rosemarie Tavaresa,et al.Stress protein expression in the Alzheimer-diseased choroid plexus.Journal of Alzheimer's Disease.2003,5(3):171-177
104.Conrad Johanson,Paul McMillan,Rosemarie Tavares,et al.Homeostatic capabilities of the choroid plexus epithelium in Alzheimer's disease.Cerebrospinal Fluid Res.2004,1(1):3
105.胡明均,刘勇,王家宁,等.热休克蛋白90alpha在血管内皮生长因子165基因治疗大鼠脑梗死中的表达及意义.上海医学.2005,28(3):233-235
106.C D Smith,J M Carney,P E Starke-Reed,et al.Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease.Proc Natl Acad Sci U S A.1991,88(23):10540-10543
107.Cooper A,Vergara F,Duffy T.Cerebral glutamine synthetase.In:Hertz L,Kvamme E,McGeer E,Schousboe A,eds.Glutamine,Glutamate,and GABA in the Central Nervous System.New York,NY:Alan R Liss Inc;1983:77-93
108.Kish S,Chang L,Dixon L,et al.Cerebellar glutamate metabolizing enzymes in spinocerebellar ataxia type I.Metab Brain Dis.1994,9(2):97-103
109.Lavoie J,Giguere J,Layrargues G,et al.Activities of neuronal and astrocytic marker enzymes in autopsied brain tissue from patients with hepatic encephalopathy.Metab Brain Dis.1987,2(4):283-290
110.LePrince G,Delaere P,Fages C,et al.Glutamine synthetase(GS) expression is reduced in senile dementia of the Alzheimer type.Neurochem Res.1995,20(7):859-862
111.Smith CD,Carney JM,Starke-Reed PE,et al.Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease.Proc Natl Acad Sci U S A.1991,88(23):10540-10543
112.Stephen R.Robinson.Changes in the cellular distribution of glutamine synthetase in Alzheimer's disease.Journal of Neuroscience Research.2001,66(5):972-980
113.D.Allan Butterfield,Kenneth Hensley,Ramela Cole,et al.Oxidatively Induced Structural Alteration of Glutamine Synthetase Assessed by Analysis of Spin Label Incorporation Kinetics:Relevance to Alzheimer's Disease.Journal of Neurochemistry.1997,68(6):2451-2457
114.Jorgensen OS,Brooksbank BW,Balázs R.Neuronal plasticity and astrocytic reaction in Down syndrome and Alzheimer disease.J Neurol Sci.1990,98(1):63-79
115.Markesbery WR,Carney JM.Oxidative alterations in Alzheimer's disease.Brain Pathol.1999,9(1):133-146
116.Burbaeva GSh,Boksha IS,Turishcheva MS,et al.Impaired cerebral glutamate metabolism in mental diseases(Alzheimer's disease,schizophrenia).Vestn Ross Akad Med Nauk.2001,(7):34-37
117.Butterfield DA.Amyloid beta-peptide(1-42)-induced oxidative stress and neurotoxicity:implications for neurodegeneration in Alzheimer's disease brain.A review.Free Radic Res.2002,36(12):1307-1313
118.Gulnur Sh.Burbaeva,Irina S.Boksha,Elena B.Tereshkina,et al.Glutamate Metabolizing Enzymes in Prefrontal Cortex of Alzheimer's Disease Patients.Neurochemical Research.2005,30(11):1443-1451
119.Stephen R.Robinson.Neuronal expression of glutamine synthetase in Alzheimer's disease indicates a profound impairment of metabolic interactions with astrocytes.Neurochemistry International.2000,36(4-5):471-482
120.Alessandra Castegna,Michael Aksenov,Marina Aksenova,et al.Proteomic identification of oxidatively modified proteins in alzheimer's disease brain.part Ⅰ:creatine kinase BB,glutamine synthase,and ubiquitin carboxy-terminal hydrolase L-1.Free Radical Biology and Medicine.2002,33(4):562-571
121.Hensley K,Hall N,Subramaniam R,et al.Brain Regional Correspondence Between Alzheimer's Disease Histopathology and Biomarkers of Protein Oxidation.J.Neurochem.1995,65(5):2146-2156
122.Hayrettin Tumani,GuoQiu Shen,James B.Peter,et al.Glutamine Synthetase in Cerebrospinal Fluid,Serum,and Brain A Diagnostic Marker for Alzheimer Disease?.Arch Neurol.1999,56(10):1241-1246
123.谢作斌,王友群.ERp29-一种新的内质网蛋白.医学综述.2009,15(3):374-377
124.HubbardMJ,Mangum JE,McHugh NJ.Purification and biochemical characterization of native ERp29 from rat liver.Biochem J.2004,383(Pt3):589-597
125.Matus S.The stress rheostat:an interp lay between the unfolded protein response(UPR)and autophagy in neurodegeneration.Curr MolMed.2008,8(3):157-172
126.Mkrtchian S,Sandalova T.ERp29,an unusual redox2inactive member of the thioredoxin family.Antioxid Redox Signal.2006,8(3-4):325-337
127.Laskey RA.Nucleosomes are assembled by an acidic p rotein which binds histones and transfers them to DNA.Nature.1978,275(5679):416-420
128.llis RJ.Molecular chaperones:assisting assembly in addition to folding.Trends Biochem Sci.2006,31(7):395-401
129.Pagani M.Endop lasmic reticulum oxidoreductin 121beta(ER012Lbeta),a human gene induced in the course of the unfolded protein response.J Biol Chem.2000,275(31):23685-23692
130.Sitia R,Braakman I.Quality control in the endop lasmic reticulump rotein factory.Nature.2003,426(6968):891-894
131.Herrmann JM,Malkus P,Schekman R.Out of the ER22outfitters,escorts and guides.Trends Cell Biol.1999,9(1):527
132.Hughes GJ,Frutiger S.Human liver p rotein map:update 1993.Electrophoresis.1993,14(11):1216-1222.
133.Bendheim PE,Bolton DC.A 54-kDa normal cellular protein may be the precursor of the scrapie agent protease-resistant protein.Proc Natl Acad Sci USA.1986,83(7):2214-2218
[1]陈主初,肖志强.疾病蛋白质组学[M].北京:化学工业出版社.2006.1-106
[2]Wasinger VC,Cordwell S J,Cerpa-Poljak A,et al.Progress with gene product mapping of the molicutes:Mycoplasma genitalium[J].Electrophoresis.1995,16(7):1090-1094
[3]钱小红,贺福初.蛋白质组学:理论与方法[M].北京:科学出版社. 2003.12-95
[4]Kim SI,Voshol H,van Oostrum J,et al.Neuroproteomics:expression profiling of the brain's proteomes in health and disease[J].Neurochem Res.2004,29(6):1317-1331
[5]Schonberger SJ,Edgar PF,Kydd R,et al.Proteomic analysis of the brain in Alzheimer's disease:Molecular phenotype of a complex disease process[J].Proteomics.2001,1(12):1519-1528
[6]Langen H,Berndt P,Roder D,et al.Two-dimensional map of human brain proteins[J].Electrophoresis.1999,20(4-5):907-916
[7]Yoo BC,Kim SH,Cairns N,et al.Deranged expression of molecular chaperones in brains of patients with Alzheimer's disease[J].Bilchemical and Biophysical Research Communications.2001,280(l):249-258
[8]Aksenov MY,Aksenova MV,Butterfield DA,et al.Protein oxidation in the brain in Alzheimer's disease[J].Neuroscience.2001,103(2):373-383
[9]Pamplona R,Dalfo E,Ayala V,et al.Proteins in human brain cortex are modified by oxidation,glycoxidation,and lipoxidation.Effects of Alzheimer disease and identification of lipoxidation targets[J].The Journal of Biological Chemistry.2005,280(22):21522-21530
[10]Korolainen MA,Goldsteins G,Nyman TA,et al.Oxidative modification of proteins in the frontal cortex of Alzheimer's disease brain[J].Neurobiology of Aging.2006,27(1):42-53
[1 l]Woltjer RL,Cimino PJ,Boutte AM,et al.Proteomic determination of widespread detergent-insolubility including Abeta but not tau early in the pathogenesis of Alzheimer's disease[J].FASEB J.2005,19(13):1923-1925
[12]Sultana R,Boyd-Kimball D,Poon HF,et al.Redox proteomics identification of oxidized proteins in Alzheimer's disease hippocampus and cerebellum:An approach to understand pathological and biochemical alterations in AD[J].Neurobiology of Aging.2006,27(11):1564-1576
[13]Porchet R,Probst A,Bouras C,et al.Analysis of glial acidic fibrillary protein in the human entorhinal cortex during aging and in Alzheimer's disease[J].Proteomics.2003,3(8):1476-1485
[14]Korolainen MA,Auriola S,Nyman TA,et al.Proteomic analysis of glial fibrillary acidic protein in Alzheimer's disease and aging brain[J]. Neurobiology of Disease.2005,20(3):858-870
[15]Wang Q,Woltjer RL,Cimino PJ,et al.Proteomic analysis of neurofibrillary tangles in Alzheimer disease identifies GAPDH as a detergent-insoluble paired helical filament tau binding protein[J].FASEB J.2005,19(7):869-871
[16]Cottrell BA,Gal van V,Banwait S,et al.A pilot proteomic study of amyloid precursor interactors in Alzheimer's disease[J].Ann Neurol.2005,58(2):277-289
[17]Sultana R,Boyd-Kimball D,Poon HF,et al.Oxidative modification and down-regulation of Pinl in Alzheimer's disease hippocampus A redox proteomics analysis[J].Neurobiology of Aging.2006,27(7):918-925
[18]Choi J,Levey AI,Weintraub ST,et al.Oxidative modifications and down-regulation of ubiquitin carboxyl-terminal hydrolase LI associated with idiopathic Parkinson's and Alzheimer's diseases[J].The Journal of Biological Chemistry.2004,279(13):13256-13264
[19]Choi J,Rees HD,Weintraub ST,et al.Oxidative modifications and aggregation of Cu,Zn-superoxide dismutase associated with Alzheimer and Parkinson diseases[J].The Journal of Biological Chemistry.2005,280(12):11648-11655
[20]Choi J,Sullards MC,Olzmann J A,et al.Oxidative damage of DJ-1 is linked to sporadic Parkinson and Alzheimer diseases[J].The Journal of Biological Chemistry.2006,281(16):10816-10824
[21]Ho L,Sharma N,Blackman L,et al.From poteomics to biomarker discovery in Alzheimer's disease[J].Brain Research Reviews.2005,48(2):360-369