摘要
第一部分BACE-1在AD病脑组织中的表达
目的：观察BACE-1在正常及阿尔茨海默病(Alzheimer's disease, AD)时的空间表达模式。
方法：收集AD或痴呆病史超过3年的病人17例,非痴呆病人14例,不同年龄(22-34岁)恒河猴7只。首先运用尼氏染色、bielschowsky银染、免疫组织化学及western blot等方法对所收集材料进行病理诊断及分组。进而对各组脑进行p-位点APP剪切酶-1(β-site APP cleavage enzyme-1, BACE-1)免疫组织化学检测,观察BACE-1在正常和异常脑内的空间表达模式。
结果：尼氏染色结果显示为结构清晰的人脑组织,老年斑和p-Tau同时存在者为AD实验组,二者均不存在者为非AD对照组。按以上标准分别将恒河猴分为老年组及正常组。分组结果显示AD实验组和非AD对照组分别有7例,恒河猴老年组3例,正常组4例。Western blot结果显示,AD实验组p-Tau、淀粉样前体蛋白(amyloid precursor protein, APP)、不同分子量BACE-1及其β位点剪切产物的蛋白表达相对于非AD对照组均有明显增加；恒河猴老年组脑内不同分子量BACE-1蛋白含量显著高于正常组。BACE-1免疫组织化学染色结果显示,非AD对照组及恒河猴正常组BACE-1的表达模式与正常小鼠相似,即最强表达在嗅球及海马苔藓纤维,脑皮质内则主要分布在神经毡内,表现为弱的类似背景染色。AD实验组及恒河猴老年组脑内BACE-1表达出现异常上调,表现为大小不一、形状各异的斑块样结构。
结论：
BACE-1的异常表达增加可能参与了AD及老年恒河猴脑内淀粉斑的形成
第二部分BACE-1上调与Aβ沉积以及失营养性轴突病变之间的关系
目的：观察AD病人及AD样恒河猴脑内BACE-1上调与Aβ沉积以及失营养性轴突病变之间的关系,揭示AD时可能的老年斑形成过程。
方法：对各组邻片进行免疫组织化学DAB双标及免疫荧光双标观察其脑内BACE-1标记的失营养性神经突起与β淀粉样蛋白(β-amyloid, Aβ), APP、早老素(presenilin-1, PS1)等AD相关分子之间的时空关系。另通过BACE-1与突触囊泡素(synaptophysin, SYN)及微管相关蛋白-2(microtubule-associated protein-2, MAP-2)的免疫双标确定失营养神经突起的性质。
结果：AD实验组免疫组织化学邻片结果显示脑内斑块少的样本BACE-1、Aβ空间上完全匹配,而斑块多的样本Aβ表达量明显高于BACE-1;恒河猴老年组免疫荧光双标结果显示异常表达增加的BACE-1定位于失营养性轴突末梢(BACE-1与SYN免疫共存),且与APP (BACE-1剪切底物)、PS1 (Aβ在γ位点的剪切酶)、Aβ等AD相关分子有免疫共存。肿胀轴突内表达上调的BACE-1与Aβ完全共存,轴突周围没有Aβ免疫阳性产物存在。随着肿胀轴突的进-步芽生长大,一些体积小的BACE-1免疫阳性神经突起簇周围可出现少量Aβ阳性产物,并随着神经突起簇的体积增大而增多。当BACE-1标记的失营养性神经突起形成大的玫瑰花瓣样结构时,其周围已有大量致密的Aβ阳性产物存在。
结论：
1.AD时过量产生的Aβ最初可能来源于失营养神经突起中的轴突成分；
2. BACE-1可能参与调节失营养性轴突产生过量Aβ。
第三部分BACE-1上调及淀粉斑形成的实验性机制探讨
目的：探讨神经元功能降低对Tg2576小鼠脑内BACE-1及老年斑形成的影响。
方法：随机获取6月龄Tg2576小鼠28只,制备左侧嗅觉功能剥夺模型以模拟AD时脑内低代谢状态,未剥夺侧(右侧)嗅球作为自身对照,存活至7、8、9、12、18、24个月。运用细胞色素C氧化酶(cytochrome c oxidase, CO)组织化学染色、免疫组织化学、western blot、ELISA等形态学、分子生物学方法观察功能剥夺对Tg2576小鼠嗅觉中枢内BACE-1及淀粉斑形成的影响。
结果：邻片对比显示单侧嗅觉剥夺Tg2576小鼠嗅球及梨状皮质内BACE-1与CO表达相反,嗅觉剥夺侧相对于未剥夺侧BACE-1表达增加,CO则表达下降,提示模型制备成功。Western blot、β位点APP剪切酶活性测定和Aβ40. Aβ42的ELISA测定结果显示剥夺侧BACE-1、β位点APP剪切酶C末端剪切产物、Aβ40、Aβ42表达均高于未剥夺侧。BACE-1及Ap免疫组织化学染色邻片对比显示：随着年龄的增长Tg2576小鼠嗅球及梨状皮质内老年斑形成逐渐增多,且斑块最先出现在梨状皮质,然后累及嗅球。BACE-1与Aβ等免疫荧光双标结果显示Tg2576小鼠嗅球及梨状皮质内BACE-1表达在失营养性轴突末梢(BACE-1与SYN免疫共存),表达增加的BACE-1与Ap免疫共存,斑块形成过程类似于第二部分。
结论：
神经元的代谢功能降低可能是引起BACE-1上调继而形成老年斑的上游机制之一。
PART I Expression of BACE-1 in Alzheimer's disease
Objective Determine the pattern of BACE-1 in the normal and AD samples.
Methods Cortical samples totally of 17 patients with clinically diagnosed as AD or with a history of dementia (>3 years) and 14 nondemented patients were available for the present study. There were 7 rhesus monkeys with different ages (22-34 years-old). Nissl staining, bielschowsky staining, immunohistochemistry and western-blot methods were used for initial neuropathological screening and to make a pathologic diagnosis and experimental grouping. Furthermore, the normal and abnormal pattern of BACE-1 were detected with the immunohistochemistry.
Results Those human cases with well preserved cortical cytoarchitecture in Nissl staining were sorted, and the cases selected for the present study met the following conditions:AD cases (n=7) showed both senile plaques and p-Tau pathology, whereas control cases (n=7) were free of either lesion. Aged group (n=3) and normal group (n=4) of monkey were evaluated using the same criterions as human samples. Western blot showed the elevations of some AD-related protein such as p-Tau, APP, BACE-1 and theβ-site cleavage APP C-terminal fragment (β-CTF) in the diseased brains relative to controls. Levels of the different molecules of BACE-1 proteins are elevated in the aged monkey cortices with cerebral plaques relative to plaques-free cases. BACE-1 immunohistochemistry staining showed that the pattern of BACE-1 was similar to the normal pattern in mouse. The strongest and distinct BACE-1 labeling was expressed in the olfactory bulb and hippocampus fibers and diffuse and in background-like neuropil reactivity occurred in the cortex. The elevation of BACE-1-ir plaques-like profile occurred in the AD and aged rhesus monkeys, appearing as different size and various shape.
Conclusion Elevation of BACE-1 maybe promote amyloid plaques formation in the AD and old rhesus monkey
PART II The relationship among elevation of BACE-1,Aβdeposition and dystrophic neurites
Objective To explore the relationship among elevation of BACE-1, A(3 deposition and dystrophic neuritis in the AD patients and AD-like rhesus monkey and reveal the potential process of amyloid pathogenesis in AD.
Methods To investigate the time-space relationship of the BACE-1-ir dystrophic neuritis with some AD-related protein such asβ-amyloid and presenilin-1 in the adjacent tissues with immunohistochemistry. In addition, the nature of the dystrophic neuritis was determined with double staining of BACE-1 with synaptophysin or microtubule-associated protein-2 (MAP-2) immunofluoresence double staining.
Results In adjacent sections from AD cases, BACE-1 labeled profiles appear to match site-specifically with plaques in the cortex with relatively mild plaque load. While in AD cortex with heavier amyloid load, BACE-1 labeled profiles appeared to be less numerous than Aβplaques. Double immunofluoresence from aged monkey case showed that elevated BACE-1 localized in the dystrophic axons (BACE-1 co-localized with SYN)and co-localized with some AD related protein such as APP (substrate of BACE-1), PS 1 (γ-secretase of APP) and Aβ. In the swollen axon, elevated BACE-1 can co-exist locally with A(3 completely and there was no any clear extracellular Aβdeposits surrounded. Among the small plaques, Aβ-ir was relatively weak and turned stronger with the continuous swelling and sprouting dystrophic neurites. When the BACE-1-labeled dystrophic neurite arranged in a rosette-like fashion, there were plenty of densed extracelluar deposition existed.
Conclusion
1. The onset of the Aβoverproduction maybe derived from the dystrophic axons
2. BACE-1 maybe modulate the dystrophic neurites and contribute to the over-load Aβ
PART III The experimental exploration about the BACE-1 elevation and amyloid plaques formation
Objective To determine reduced neuronal activity promote BACE-1 and the amyloid plaques formation in Tg2576 mouse olfactory centers
Methods Adult Tg2576 mice (n=28) were subjected to the unilateral naris-occlusion on 6 month-old, occluded animals were allowed to survive until 7,8,9,12,18,24 months-old. CO staining, immunohistochemistry, western blot and ELISA were used for detecting the effect of the functional deprivation on the expression of BACE-1 and amyloid plaques in Tg2576 mouse olfactory centers.
Results Adjacent sections revealed an inverse modulation between BACE-land CO reactivities in the olfactory bulb and piriform cortex. BACE-1 immunoreactivity is clearly stronger while CO reactivity is clearly lower on the deprived side, which meaned the animal model is successful. Elevations of BACE-1 proteins, enzymatic activity and immediate and end products ofβ-cleavage pathway of APP can be seen in the deprived olfactory bulbs relative to counterparts. The adjacent sections of BACE-1 and A(3 immunohistochemistry staining showed that the amyloid pathogenesis in Tg2576 mouse olfactory bulbs and piriform cortex is age-dependency. BACE-1 labeled neuritis and A(3 deposition occurred firstly in the piriform cortex and then in the bulb. Double immunofluoresence staining of BACE-land Aβrevealed that BACE-1 localized in the dystrophic axons (BACE-1 and SYN colocalization) in Tg2576 mouse olfactory bulbs and piriform cortex. Elevation of BACE-1 colocalized with A(3 and the amyloid plaques formation was similar to Part II.
Conclusion
Lower neuronal activity/hypometablolism maybe one of the upstream mechanisms of BACE-1 elevation and amyloid plaques formation
引文
[1]Selkoe DJ. Amyloid protein and Alzheimer's disease. Sci Am,1991,265 (5):68-71,74-6,78
[2]Knopman DS, Parisi JE, Salviati A,et al. Neuropathology of cognitively normal elderly. Neuropathol Exp Neurol,2003,62(11):1087-95
[3]Blennow K, de Leon MJ, Zetterberg H. Alzheimer's disease. Lancet,2006. 368(9533):387-403
[4]Luo X, Yan R. Inhibition of BACE-1 for therapeutic use in Alzheimer's disease. Int J Clin Exp Pathol,20103(6):618-28
[5]Dickson DW. The pathogenesis of senile plaques. J Neuropathol Exp Neurol, 1997,56(4):321-39
[6]Selkoe DJ. Toward a comprehensive theory for Alzheimer's disease Hypothesis: Alzheimer's disease is caused by the cerebral accumulation and cytotoxicity of amyloid beta-protein. Ann N Y Acad Sci,2000,924:17-25
[7]Ferri CP, Prince M, Brayne C,et al. Alzheimer's Disease International Global prevalence of dementia:a Delphi consensus study. Lancet,2005,366(9503):2112-7
[8]Glenner GG, Wong CW. Alzheimer's disease:initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun,1984,120(3):885-90
[9]Glenner GG, Wong CW. Alzheimer's disease and Down's syndrome:sharing of a unique cerebrovascular amyloid fibril protein. Biochem Biophys Res Commun,1984, 122(3):1131-5
[10]Glenner GG and W. CW., Alzheimer's disease:initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun.,1984,120(3):885-890
[11]Fiala JC. Mechanisms of amyloid plaque pathogenesis. Acta Neuropathol, 2007,114(6):551-71
[12]Duyckaerts C, Delatour B, Potier MC. Classification and basic pathology of Alzheimer disease. Acta Neuropathol,2009,118(1):5-36
[13]Miyakawa T, S.A., Kuramoto R, Higuchi Y. The relationship between senile plaques and cerebral blood vessels in Alzheimer's disease and senile dementia Morphological mechanism of senile plaque production. Virchows Arch B Cell Pathol Incl Mol Pathol,1 982,40(2):121-9
[14]Kawai M, Cras P, Perry G. Serial reconstruction of beta-protein amyloid plaques:relationship to microvessels and size distribution. Brain Res,1992,592 (1-2):278-82
[15]Arends YM, Duyckaerts C, Rozemuller JM, et al. Microglia, amyloid and dementia in alzheimer disease. A correlative study. Neurobiol Aging,2000,21(1):39-47
[16]Arendt T. Alzheimer's disease as a disorder of dynamic brain self-organization. Prog Brain Res,2005,147:355-78
[17]Tuppo EE, Arias HR. The role of inflammation in Alzheimer's disease. Int J Biochem Cell Biol,2005,37(2):289-305
[18]Armstrong RA. The molecular biology of senile plaques and neurofibrillary tangles in Alzheimer's disease. Folia Neuropathol,2009,47(4):289-99.
[19]Hardy JA, Higgins GA. Alzheimer's disease:the amyloid cascade hypothesis. Science,1 992,256(5054):184-5
[20]Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease:progress and problems on the road to therapeutics. Science,2002,297(5580):353-6
[21]Wolfe MS, Xia W, Ostaszewski BL,et al. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature, 1999,398(6727):513-7
[22]Fryer JD, Simmons K, Parsadanian M,et al. Human apolipoprotein E4 alters the amyloid-beta 40:42 ratio and promotes the formation of cerebral amyloid angiopathy in an amyloid precursor protein transgenic model. JNeurosci,2005,25(11):2803-10
[23]Davies P, Koppel J. Mechanism-based treatments for Alzheimer's disease. Dialogues Clin Neurosc,2009,11 (2):159-69
[24]Neugroschl J, Sano M. Current treatment and recent clinical research in Alzheimer's disease. Mt Sinai J Med,2010,77(1):3-16
[25]Miners JS, van Helmond Z, Kehoe PG, et al. Changes with age in the activities of beta-secretase and the Abeta-degrading enzymes neprilysin, insulin-degrading enzyme and angiotensin-converting enzyme. Brain Pathol,2010,20(4):794-802
[26]Solomon B, Frenkel D. Immunotherapy for Alzheimer's disease. Neuropharmacology,2010,59(4-5):303-9
[27]Tabira T. Immunization therapy for Alzheimer disease:a comprehensive review of active immunization strategies. Tohoku J Exp Med,2010,220(2):95-106
[28]Struble RG, Ala T., Patrylo PR. Is Brain Amyloid Production a Cause or a Result of Dementia ofThe Alzheimer's Type? J Alzheimers Dis,2010,Aug 30
[29]Castellani RJ, Lee HG, Siedlak SL,et al. Reexamining Alzheimer's disease: evidence for a protective role for amyloid-beta protein precursor and amyloid-beta. J Alzheimers Dis,2009,1 8(2):447-52
[30]Terry, R.D.& Wisniewski H.M. The ultrastructure of the neurobrillary tangle and the senile plaque. In Wolstenholme, G.E.W.& O'Connor, M. (Eds),Alzheimer's Disease and Related Conditions. J&A Churchill,London,pp.145-168
[31]Gouras GK, Almeida CG, Takahashi RH. Intraneuronal Abeta accumulation and origin of plaques in Alzheimer's disease. Neurobiol Aging,2005,26(9):1235-44
[32]Fiala JC. Mechanisms of amyloid plaque pathogenesis. Acta Neuropathol,2007, 114(6):551-71
[33]Lazarov O, Lee M, Peterson DA, Sisodia SS. Evidence that synaptically released beta-amyloid accumulates as extracellular deposits in the hippocampus of transgenic mice. J Neurosci,2002,22(22):9785-93
[34]Sheng JG, Price DL, Koliatsos VE. Disruption of corticocortical connections ameliorates amyloid burden in terminal fields in a transgenic model of Abeta amyloidosis. J Neurosci,2002,22(22):9794-9
[35]Sheng JG, Price DL, Koliatsos VE. The beta-amyloid-related proteins presenilin 1 and BACE-1 are axonally transported to nerve terminals in the brain. Exp Neurol,2003,184(2):1053-7
[36]Zhao J, Fu Y, Yasvoina M,et al. Beta-site amyloid precursor protein cleaving enzyme 1 levels become elevated in neurons around amyloid plaques:implications for Alzheimer's disease pathogenesis. J Neurosci,2007,27(14):3639-49
[37]Selkoe DJ. Alzheimer's disease results from the cerebral accumulation and cytotoxicity of amyloid beta-protein. J Alzheimers Dis,2001,3(1):75-80
[38]Li R, Lindholm K, Yang LB,et al. Amyloid beta peptide load is correlated with increased beta-secretase activity in sporadic Alzheimer's disease patients. Proc Natl Acad SciUSA.,2004,101(10):3632-7
[39]Hardy J, A.D., Amyloid deposition as the central event in the aetiology of Alzheimer's disease. Trends Pharmacol Sci,1991,12(10):383-8
[40 ]Thinakaran G, Koo EH. Amyloid precursor protein trafficking, processing, and function. J Biol Chem,2008,283(44):29615-9
[41]Kametani F. Epsilon-secretase:reduction of amyloid precursor protein epsilon-site cleavage in Alzheimer's disease. Curr Alzheimer Res,2008,5(2):165-71
[42]Hussain I, Powell D, Howlett DR,et al. Identification of a novel aspartic protease (Asp 2) as beta-secretase. Mol Cell Neurosci,1999,14(6):419-27
[43]Sinha S, Anderson JP, Barbour R,et al. Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature,1999,402(6761):537-40
[44]Vassar R, Bennett BD, Babu-Khan S,et al. Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science,1999,286(5440):735-41
[45]Yan R, Bienkowski MJ, Shuck ME,et al. Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity. Nature,1999,402(6761):533-7
[46]Haniu M, Denis P, Young Y,et al. Characterization of Alzheimer's beta-secretase protein BACE. A pepsin family member with unusual properties. J Biol Chem, 2000,275(28):21099-106
[47]Zhong Z, Ewers M, Teipel S,et al. Levels of beta-secretase (BACE-1) in cerebrospinal fluid as a predictor of risk in mild cognitive impairment. Arch Gen Psychiatry,2007,64(6):718-26
[48]Ewers M, Zhong Z, Burger K,et al. Increased CSF-BACE 1 activity is associated with ApoE-epsilon 4 genotype in subjects with mild cognitive impairment and Alzheimer's disease. Brain Pathol,131(Pt 5):1252-8
[49]Zetterberg H, Andreasson U, Hansson O,et al. Elevated cerebrospinal fluid BACE-1 activity in incipient Alzheimer disease. Arch Neurol,2008,65(8):1102-7
[50]Vassar R, Kovacs DM, Yan R,et al. The beta-secretase enzyme BACE in health and Alzheimer's disease:regulation, cell biology, function, and therapeutic potential. J Neurosci,2009,29(41):12787-94
[51]Mulder SD, van der Flier WM, Verheijen JH,et al. BACE-1 activity in cerebrospinal fluid and its relation to markers of AD pathology. J Alzheimers Dis,2010, 20(1):253-60
[52]Zhang XM, Cai Y, Xiong K,et al. Beta-secretase-1 elevation in transgenic mouse models of Alzheimer's disease is associated with synaptic/axonal pathology and amyloidogenesis:implications for neuritic plaque development. Eur J Neurosci,2009, 30(12):2271-83
[53]Zhang XM, Xiong K, Cai Y,et al. Functional deprivation promotes amyloid plaque pathogenesis in Tg2576 mouse olfactory bulb and piriform cortex. Eur J Neurosci,2010,31(4):710-21
[54]Schwab C, Hosokawa M, McGeer PL. Transgenic mice overexpressing amyloid beta protein are an incomplete model of Alzheimer disease. Exp Neurol, 2004,188(1):52-64
[55]Reiman EM, Caselli RJ, Chen K,et al. Declining brain activity in cognitively normal apolipoprotein E epsilon 4 heterozygotes:A foundation for using positron emission tomography to efficiently test treatments to prevent Alzheimer's disease. Proc Natl Acad Sci U S A,2001,98(6):3334-9
[56]Nestor PJ, Fryer TD, Smielewski P,et al. Limbic hypometabolism in Alzheimer's disease and mild cognitive impairment. Ann Neurol,2003,54(3):343-51
[57]Perneczky R, Hartmann J, Grimmer T,et al. Cerebral metabolic correlates of the clinical dementia rating scale in mild cognitive impairment. J Geriatr Psychiatry Neurol,2007,20(2):84-8
[58]Kemppainen NM, Aalto S, Karrasch M,et al. Cognitive reserve hypothesis: Pittsburgh Compound B and fluorodeoxyglucose positron emission tomography in relation to education in mild Alzheimer's disease. Ann Neurol,2008,63(1):112-8
[59]Fratiglioni L, Wang HX. Brain reserve hypothesis in dementia. J Alzheimers Dis,2007,12(1):11-22
[60]Roe CM, Xiong C, Miller JP,et al. Interaction of neuritic plaques and education predicts dementia. Alzheimer Dis Assoc Disord,2008,22(2):188-93
[61]Lazarov O, Robinson J, Tang YP,et al. Environmental enrichment reduces Abeta levels and amyloid deposition in transgenic mice. Cell,2005,120(5):701-13
[62]Jankowsky JL, Melnikova T, Fadale DJ,et al. Environmental enrichment mitigates cognitive deficits in a mouse model of Alzheimer's disease. J Neurosci, 2005,25(21):5217-24
[63]Billings LM, Green KN, McGaugh JL,et al. Learning decreases Abeta*56 and tau pathology and ameliorates behavioral decline in 3xTg-AD mice. J Neurosci,2007, 27(4):751-61
[64]Yan XX, Xiong K, Luo XG,et al. beta-Secretase expression in normal and functionally deprived rat olfactory bulbs:inverse correlation with oxidative metabolic activity. J Comp Neurol,2007,501(1):52-69
[65]刘冬戈,吴浩强,满开泉,等.阿尔茨海默病患者脑组织病理形态学及β-淀粉样蛋白免疫组织化学观察.中华病理学杂志,1999,28(6)：405-408
[66]Yang GB, Lackner AA. Proximity between 5-HT secreting enteroendocrine cells and lymphocytes in the gut mucosa of rhesus macaques (Macaca mulatta) is suggestive of a role for enterochromaffin cell 5-HT in mucosal immunity. J Neuroimmunol,2004,146(1-2):46-9
[67]Harada H, Tamaoka A, Ishii K,et al. Expression of mRNA for multiple serotonin (5-HT) receptor types/subtypes by the peripheral blood mononuclear cells of rhesus macaques. J Neuroimmunol,2006,178(1-2):24-9
[68]Price DL, Martin LJ, Sisodia SS,et al. Aged non-human primates:an animal model of age-associated neurodegenerative disease. Brain Pathol,1991,1(4):287-96
[69]Beal MF, W.L., Storey E, Segar L, Price DL, Cork LC., Neurotransmitters in neocortex of aged rhesus monkeys. Neurobiol Aging,1991,12(5):407-12
[70]Sani S, Traul D, Klink A,et al. Distribution, progression and chemical composition of cortical amyloid-beta deposits in aged rhesus monkeys:similarities to the human. Acta Neuropathol,2003,105(2):145-56
[71]Fukumoto H, Cheung BS, Hyman BT,et al. Beta-secretase protein and activity are increased in the neocortex in Alzheimer disease. Arch Neurol,2002,59(9):1381-9
[72]Holsinger RM, McLean CA, Beyreuther K,et al. Increased expression of the amyloid precursor beta-secretase in Alzheimer's disease. Ann Neurol,2002,51 (6):783-6
[73]Tyler SJ, Dawbarn D, Wilcock GK,et al. alpha-and beta-secretase:profound changes in Alzheimer's disease. Biochem Biophys Res Commun,2002,299(3):373-6
[74]Yang LB, Lindholm K, Yan R,et al. Elevated beta-secretase expression and enzymatic activity detected in sporadic Alzheimer disease. Nat Med,2003,9(1):3-4
[75]Hampel H, Shen Y. Beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1) as a biological candidate marker of Alzheimer's disease. Scand J Clin Lab Invest,2009,69(1):8-12
[76]Chu Y, Kordower JH. Age-associated increases of alpha-synuclein in monkeys and humans are associated with nigrostriatal dopamine depletion:Is this the target for Parkinson's disease? Neurobiol Dis,2007,25(1):134-49
[77]熊鲲,黄河,王慧,等.不同浓度SDS在大鼠FFPE脑组织提取BACE-1的实验研究.解剖学杂志,2008,31(6)：761-763
[78]Santpere G, Puig B, Ferrer I,et al. Low molecular weight species of tau in Alzheimer's disease are dependent on tau phosphorylation sites but not on delayed post-mortem delay in tissue processing. Neurosci Lett,2006,399(1-2):106-10
[79]Cai H, Wang Y, McCarthy D,et al. BACE-1 is the major beta-secretase for generation of Abeta peptides by neurons. Nat Neurosci,2001,4(3):233-4
[80]Xiong K, Cai H, Luo XG,et al. Mitochondrial respiratory inhibition and oxidative stress elevate beta-secretase (BACE-1) proteins and activity in vivo in the rat retina. Exp Brain Res,2007,181(3):435-46
[81]Wang L, Shim H, Xie C,et al. Activation of protein kinase C modulates BACE-1-mediated beta-secretase activity. Neurobiol Aging,2008,29(3):357-67
[82]McDonald JK, Tigges J, Tigges M,et al. Developmental study of neuropeptide Y-like immunoreactivity in the neurohypophysis and intermediate lobe of the rhesus monkey (Macaca mulatta). Cell Tissue Res,1988,254(3):499-509
[83]Luebke J, Barbas H, Peters A. Effects of normal aging on prefrontal area 46 in the rhesus monkey. Brain Res Rev,2010,62(2):212-32
[84]Heilbroner PL, Kemper TL. The cytoarchitectonic distribution of senile plaques in three aged monkeys. ActaNeuropathol,1990,81 (1):60-5
[85]Ng KH, Tan KL, Gan SK,et al. Immunolabelling of prolactin at ultrastructural level using the protein A-gold technique on Epon-embedded tissue. Malays J Pathol, 1992,14(1):29-33
[86]Yang GB, Qiu CL, Zhao H,et al. Beta-site APP cleaving enzyme 1 (BACE-1) is increased in remaining neurons in Alzheimer's disease brains. Neurosci Res,2006, 54(1):24-9
[87]Spires TL, Meyer-Luehmann M, Stern EA,et al. Dendritic spine abnormalities in amyloid precursor protein transgenic mice demonstrated by gene transfer and intravital multiphoton microscopy. J Neurosci,2005,25(31):7278-87
[88]Knafo S, Alonso-Nanclares L, Gonzalez-Soriano J,et al. Widespread changes in dendritic spines in a model of Alzheimer's disease. Cereb Cortex,2009,19(3):586-92
[89]Stokin GB, Lillo C, Falzone TL,et al. Axonopathy and transport deficits early in the pathogenesis of Alzheimer's disease. Science,2005,307(5713):1282-8
[90]Li S, Hong S, Shepardson NE,et al. Soluble oligomers of amyloid Beta protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake. Neuron,2009,62(6):788-801
[91]Moreno H, Yu E, Pigino G,et al. Synaptic transmission block by presynaptic injection of oligomeric amyloid beta. Proc Natl Acad Sci U S A,2009,106(14):5901-6
[92]Nimmrich V, Ebert U. Is Alzheimer's disease a result of presynaptic failure? Synaptic dysfunctions induced by oligomeric beta-amyloid. Rev Neurosci,2009,20 (1):1-12
[93]Chow VW, Savonenko AV, Melnikova T,et al. Modeling an anti-amyloid combination therapy for Alzheimer's disease. Sci Transl Med,2010,2(13):13ral
[94]De Strooper B. Proteases and proteolysis in Alzheimer disease:a multifactorial view on the disease process. Physiol Rev,2010,90(2):465-94.
[95]Zhang XM, Xiong K, Cai Y,et al. Functional deprivation promotes amyloid plaque pathogenesis in Tg2576 mouse olfactory bulb and piriform cortex. Eur J Neurosci.,2010,31(4):710-21
[96]Lazarov O, Robinson J, Tang YP,et al. Environmental enrichment reduces Abeta levels and amyloid deposition in transgenic mice. Cell,2005,120 (5):701-13
[97]Billings LM, Green KN, McGaugh JL,et al. Learning decreases Abeta*56 and tau pathology and ameliorates behavioral decline in 3xTg-AD mice. J Neurosci, 2007,27(4):751-61
[98]Knopman DS, Parisi JE, Salviati A,et al. Expression of the amyloid protein precursor of Alzheimer's disease in the developing rat olfactory system. Dev Brain Research,1995,88(1):1087-95
[99]Kim HH, Puche AC, Margolis FL. Odorant deprivation reversibly modulates transsynaptic changes in the NR2B-mediated CREB pathway in mouse piriform cortex. J Neurosci,2006,26(37):9548-59
[100]Hsiao K, Chapman P, Nilsen S,et al. Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science,1996,274(5284):99-102
[101]Sarsoza F, Saing T, Kayed R,et al. A fibril-specific, conformation-dependent antibody recognizes a subset of Abeta plaques in Alzheimer disease, Down syndrome and Tg2576 transgenic mouse brain. Acta Neuropathol,2009,1 18(4):505-17
[102]Johnson BA, Leon M. Chemotopic odorant coding in a mammalian olfactory system. J Comp Neurol,2007,503(1):1-34
[103]Oka Y, Takai Y, Touhara K. Nasal airflow rate affects the sensitivity and pattern of glomerular odorant responses in the mouse olfactory bulb. J Neurosci, 2009,29(39):12070-8
[104]Wesson DW, Verhagen JV, Wachowiak M. Why sniff fast? The relationship between sniff frequency, odor discrimination, and receptor neuron activation in the rat. J Neurophysiol,2009,101(2):1089-102.
[105]Cullinan WE, Brunjes PC. Unilateral odor deprivation:effects on the development of staining for olfactory bulb succinate dehydrogenase. Brain Res,1987, 432(l):35-42
[106]Jin BK, Franzen L, Baker H. Regulation of c-Fos mRNA and fos protein expression in olfactory bulbs from unilaterally odor-deprived adult mice. Int J Dev Neurosci,1996,14(7-8):971-82
[107]Philpot BD, Foster TC, Brunjes PC. Mitral/tufted cell activity is attenuated and becomes uncoupled from respiration following naris closure. J Neurobiol,1997, 33(4):374-86
[108]Struble RG, Powers RE, Casanova MF, et al. Neuropeptidergic systems in plaques of Alzheimer's disease. J Neuropathol Exp Neurol,1987,46(5):567-84
[109]Bell KF, Ducatenzeiler A, Ribeiro-da-Silva A,et al. The amyloid pathology progresses in a neurotransmitter-specific manner. Neurobiol Aging,2006,27(11): 1644-57
[110]Nakamura K, Hioki H, Fujiyama F, et al. Postnatal changes of vesicular glutamate transporter (VGluT)1 and VGluT2 immunoreactivities and their colocalization in the mouse forebrain. J Comp Neurol,2005,492(3):263-88
[111]De Olmos J, Hardy H, Heimer L. The afferent connections of the main and the accessory olfactory bulb formations in the rat:an experimental HRP-study. J Comp Neurol,1978,181 (2):213-44
[112]Najbauer J, Yan XX, Leon M. Internucleosomal DNA fragmentation during deprived and non-deprived olfactory development. Brain Res,2002,926(1-2):118-25
[113]Xiong K, Luo DW, Patrylo PR,et al. Doublecortin-expressing cells are present in layer II across the adult guinea pig cerebral cortex:partial colocalization with mature interneuronmarkers. ExpNeurol,2008,21 1(1):271-82
[114]Martinez Garcia MC, Cuervas-Mons Finat M, Latorre Macarron E,et al. Responses of the astroglia in sensory deprived olfactory bulb of developing rats. Histol Histopathol, 991,6(2):235-9
[115]Velliquette RA, O'Connor T, Vassar R. Energy inhibition elevates beta-secretase levels and activity and is potentially amyloidogenic in APP transgenic mice: possible early events in Alzheimer's disease pathogenesis. J Neurosci,2005,25 (47): 10874-83
[116]Dong Y, Zhang G, Zhang B,et al. The common inhalational anesthetic sevoflurane induces apoptosis and increases beta-amyloid protein levels. Arch Neurol, 2009,66(5):620-31
[1]Selkoe DJ. Amyloid protein and Alzheimer's disease. Sci Am,1991, 265(5):68-71,74-76,78
[2]Knopman DS,Parisi JE,Salviati A,et al. Neuropathology of cognitively normal elderly. J Neuropathol Exp Neurol,2003,62(11):1087-1095
[3]Blennow K, de Leon MJ, Zetterberg H. Alzheimer's disease. Lancet, 2006,368(9533):387-403
[4]Luo X, Yan R. Inhibition of BACE-1 for therapeutic use in Alzheimer's disease. Int J Clin Exp Pathol,2010,3(6):618-628
[5]Braak H, Braak E. Evolution of the neuropathology of Alzheimer's disease. ActaNeurol Scand Suppl,1996,165:3-12
[6]Dickson DW. The pathogenesis of senile plaques. J Neuropathol Exp Neurol, 1997,56(4):321-339
[7]Selkoe DJ. Toward a comprehensive theory for Alzheimer's disease. Hypothesis:Alzheimer's disease is caused by the cerebral accumulation and cytotoxicity of amyloid beta-protein. Ann N Y Acad Sci,2000,924:17-25
[8]Brookmeyer R, J.E., Ziegler-Graham K, et al. Forecasting the global burden of Alzheimer's disease. Alzheimers Dement,2007,3(3):186-191
[9]Ferri CP, P.M., Brayne C, Brodaty H, et al. Alzheimer's Disease International.Global prevalence of dementia:a Delphi consensus study. Lancet,2005, 366(9503):2112-2117
[10]Wimo A,Jonsson L, W. B.. An estimate of the worldwide prevalence and direct costs of dementia in 2003. Dement Geriatr Cogn Disord,2006,21(3):175-181
[11]Ayres JW, Lorskulsint D, Lock A, et al. Absorption and distribution of radioactivity from suppositories containing 3H-benzocaine in rats. Ann N Y Acad Sci,1997,826:25-34
[12]Glenner GG, Wong CW. Alzheimer's disease and Down's syndrome:sharing of a unique cerebrovascular amyloid fibril protein. Biochem Biophys Res Commun, 1984,122(3):1131-1135
[13]Hardy JA, Higgins GA. Alzheimer's disease:the amyloid cascade hypothesis. Science,1992,256(5054):184-185
[14]Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease:progress and problems on the road to therapeutics. Science,2002,297(5580):353-356
[15]Glenner GG, W. CW. Alzheimer's disease:initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun,1984,120(3):885-890
[16]Armstrong RA. The molecular biology of senile plaques and neurofibrillary tangles in Alzheimer's disease. Folia Neuropathol,2009,47(4):289-299
[17]WolfeMS. Shutting down Alzheimer's. Sci Am,2006,294(5):72-79
[18]Kametani F. Epsilon-secretase:reduction of amyloid precursor protein epsilon-site cleavage in Alzheimer's disease. Curr Alzheimer Res,2008,5(2):165-171
[19]Hardy J, Allsop D. Amyloid deposition as the central event in the aetiology of Alzheimer's disease. Trends Pharmacol Sci,1991,12(10):383-388
[20]Thinakaran G, Koo EH. Amyloid precursor protein trafficking, processing, and function. J Biol Chem,2008,283(44):29615-29619
[21]Selkoe DJ. Alzheimer's disease results from the cerebral accumulation and cytotoxicity of amyloid beta-protein. J Alzheimers Dis,2001,3(1):75-80
[22]郁向静,何俊民.β-淀粉样蛋白在阿尔茨海默病中的病因学作用.临床和实验医学杂志,2007,6(2)：147-148
[23]Duyckaerts C, Delatour B, Potier MC. Classification and basic pathology of Alzheimer disease. Acta Neuropathol,2009,118(1):5-36
[24]Funderburk SF,Marcellino BK,Yue Z. Cell "self-eating" (autophagy) mechanism in Alzheimer's disease. Mt Sinai J Med,2010,77(1):59-68
[25]He C, Levine B. The Beclin 1 interactome. Curr Opin Cell Biol,2010, 22(2):140-149
[26]Pickford F, Masliah E, Britschgi M,et al. The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J Clin Invest,2008,118(6):2190-2199
[27]Shibata M, Yamada S, Kumar SR, et al. Clearance of Alzheimer's amyloid-ss(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. J Clin Invest,2000,106(12):1489-1499
[28]Cirrito JR, Deane R, Fagan AM, et al. P-glycoprotein deficiency at the blood-brain barrier increases amyloid-beta deposition in an Alzheimer disease mouse model. J Clin Invest,2005,115(11):3285-3290
[29]Deane R, Du Yan S, Submamaryan RK,et al. RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nat Med, 2003,9(7):907-913
[30]Alvira-Botero X, Carro EM. Clearance of Amyloid-Peptide Across the Choroid Plexus in Alzheimer's Disease. Curr Aging Sci,2010.
[31]Fisher Y. T cells specifically targeted to amyloid plaques enhance plaque clearance in a mouse model of Alzheimer's disease. PLoS One,2010,5(5):10830
[32]Walsh DM, Selkoe DJ. A beta oligomers-a decade of discovery. J Neurochem,2007,101 (5):1172-1184
[33]Gearing M, Tigges J, Mori H,et al. Abeta40 is a major form of beta-amyloid in nonhuman primates. Neurobiol Aging,1996,17(6):903-908
[34]Selkoe DJ, Yamazaki T, Citron M,et al. The role of APP processing and trafficking pathways in the formation of amyloid beta-protein. Ann N Y Acad Sci, 1996,777:57-64
[35]Walsh DM, Tseng BP, Rydel RE,et al. The oligomerization of amyloid beta-protein begins intracellularly in cells derived from human brain. Biochemistry, 2000,39(35):10831-10839
[36]Cuello AC. Intracellular and extracellular Abeta, a tale of two neuropathologies. Brain Pathol,2005,15(1):66-71
[37]Pleckaityte M. Alzheimer's disease:a molecular mechanism, new hypotheses, and therapeutic strategies. Medicina (Kaunas),2010,46(1):70-76
[38]Smith DG, Cappai R, Barnham KJ. The redox chemistry of the Alzheimer's disease amyloid beta peptide. Biochim Biophys Acta,2007,1768(8):1976-1990
[39]Bitan G, Kirkitadze MD, Lomakin A,et al. Amyloid beta-protein (Abeta) assembly:Abeta43 is more frequent than Abeta40 in amyloid plaque cores from Alzheimer disease brains. J Neurochem,2009,1 10(2):697-706
[40]Sarsoza F, Saing T, Kayed R, et al. A fibril-specific, conformation-dependent antibody recognizes a subset of Abeta plaques in Alzheimer disease, Down syndrome and Tg2576 transgenic mouse brain. Acta Neuropathol,2009,118(4):505-517
[41]Hartig W, Kacza J, Paulke BR,et al. In vivo labelling of hippocampal beta-amyloid in triple-transgenic mice with a fluorescent acetylcholinesterase inhibitor released from nanoparticles. Eur J Neurosci,2010,31(1):99-109
[42]Portelius E, Bogdanovic N, Gustavsson MK, et al. Mass spectrometric characterization of brain amyloid beta isoform signatures in familial and sporadic Alzheimer's disease. Acta Neuropathol,2010,120(2):185-193
[43]Van Helmond Z, Miners JS, Kehoe PG,et al. Higher soluble amyloid beta concentration in frontal cortex of young adults than in normal elderly or Alzheimer's disease.Brain Pathol,2010,20(4):787-793
[44]Dickson TC, V. JC. The morphological phenotype of beta-amyloid plaques and associated neuritic changes in Alzheimer's disease. Neuroscience,2001,105 (1):99-107
[45]Thal DR, Capetillo-Zarate E, Del Tredici K, et al. The development of amyloid beta protein deposits in the aged brain. Sci Aging Knowledge Environ,2006, (6):rel
[46]Busciglio J,Lorenzo A, Y. BA. Methodological variables in the assessment of beta amyloid neurotoxicity. Neurobiol Aging,1992,13(5):609-612
[47]Katzman R. Clinical, pathological, and neurochemical changes in dementia: a subgroup with preserved mental status and numerous neocortical plaques. Ann Neurol,1988,23(2):138-144
[48]Terry RD. Neuropathological changes in Alzheimer disease. Prog Brain Res,1 994,101:383-390
[49]Lambert MP, Barlow AK, Chromy BA,et al. Diffusible, nonfibrillar ligands derived from Abeta 1-42 are potent central nervous system neurotoxins. Proc Natl AcadSciUSA,1998,95(11):6448-6453
[50]Dodart JC, Bales KR, Gannon KS,et al. Immunization reverses memory deficits without reducing brain Abeta burden in Alzheimer's disease model. Nat Neurosci,2002,5(5):452-457
[51]Oddo S, Vasilevko V, Caccamo A, et al. Reduction of soluble Abeta and tau, but not soluble Abeta alone, ameliorates cognitive decline in transgenic mice with plaques and tangles. J Biol Chem.2006,281(51):39413-39423
[52]Lesne S, Koh MT, Kotilinek L, Kayed R, et al. A specific amyloid-beta protein assembly in the brain impairs memory. Nature,2006,440(7082):352-357
[53]Xia W. Brain amyloid β protein and memory disruption in Alzheimer's disease. Neuropsychiatr Dis Treat.,2010,6:605-611
[54]Walsh DM, S. DJ., Oligomers on the brain:the emerging role of soluble protein aggregates in neurodegeneration. Protein Pept Lett.,2004,11(3):213-228
[55]Townsend M, Shankar GM, Mehta T, et al. Effects of secreted oligomers of amyloid beta-protein on hippocampal synaptic plasticity:a potent role for trimers. J Physiol.,2006,572(2):477-492
[56]Selkoe DJ. Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior. Behav Brain Res.,2008,192(1):106-113
[57]Klyubin I, Betts V, Welzel AT, et al. Amyloid beta protein dimer-containing human CSF disrupts synaptic plasticity:prevention by systemic passive immunization. JNeurosci.,2008,28(16):4231-4237
[58]Ono K, Condron MM, and T. DB., Structure-neurotoxicity relationships of amyloid beta-protein oligomers.Proc Natl Acad Sci U S A.,2009,106 (35): 14745-14750
[59]孔繁军,韩晓涛,张茁,等.β-淀粉样蛋白与阿尔茨海默病神经元退变的研究现状.神经疾病与精神卫生,2007,7(6)：459-460
[60]Cirrito JR, May PC, O'Dell MA, et al., In vivo assessment of brain interstitial fluid with microdialysis reveals plaque-associated changes in amyloid-beta metabolism and half-life. J Neurosci.,2003,23(26):8844-8853
[61]Yankner BA, Duffy LK, Kirschner DA. Neurotrophic and neurotoxic effects of amyloid beta protein:reversal by tachykinin neuropeptides. Science,1990,250 (4978):279-282
[62]Plant LD, Boyle JP, Smith IF, et al. The production of amyloid beta peptide is a critical requirement for the viability of central neurons. J Neurosci.,2003,23 (13): 5531-5535
[63]Lopez-Toledano MA, Shelanski ML. Neurogenic effect of beta-amyloid peptide in the development of neural stem cells. J Neurosci.,2004,24(23):5439-5444
[64]Puzzo D, Privitera L, Leznik E, et al., Picomolar amyloid-beta positively modulates synaptic plasticity and memory in hippocampus. J Neurosci.,2008,28 (53): 14537-14545
[65]Haass C, Selkoe DJ. Soluble protein oligomers in neurodegeneration:lessons from the Alzheimer's amyloid beta-peptide. Nat Rev Mol Cell Biol.,2007,8(2): 101-112
[66]Harvey RJ, Skelton-Robinson M, Rossor MN. The prevalence and causes of dementia in people under the age of 65 years. J Neurol Neurosurg Psychiatry.,2003, 74(9):1206-1209
[67]Wolfe MS, Xia W, Ostaszewski BL,et al., Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature,1999,398(6727):513-517
[68]Sherrington R, Rogaev El, Liang Y, et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature,1995,375 (6534):754-760
[69]De Strooper B, Saftig P, Craessaerts K, et al. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature,1998,391 (6665): 387-390
[70]Fryer JD, et al. Human apolipoprotein E4 alters the amyloid-beta 40:42 ratio and promotes the formation of cerebral amyloid angiopathy in an amyloid precursor protein transgenic model. J Neurosci.,2005,25(11):2803-2810
[71]Campion D, D.C., Hannequin D, Dubois B,et al. Early-onset autosomal dominant Alzheimer disease:prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet.,1999,65(3):664-670
[72]Davies P and K. J., Mechanism-based treatments for Alzheimer's disease. Dialogues Clin Neurosci.,2009,11(2):159-169
[73]Seripa D, et al., Non-apolipoprotein E and apolipoprotein E genetics of sporadic Alzheimer's disease. Ageing Res Rev.,2009,8(3):214-236
[74]Wang M, Song H, Jia J. Interleukin-6 receptor gene polymorphisms were associated with sporadic Alzheimer's disease in Chinese Han. Brain Res., 2010,1327:1-5.
[75]Yuan Q, Zuo X, Jia J. Association between promoter polymorphisms of vascular endothelial growth factor gene and sporadic Alzheimer's disease among Northern Chinese Han. Neurosci Lett.,2009,457(3):133-136
[76]Xue S, Jia L, Jia J. Association between somatostatin gene polymorphisms and sporadic Alzheimer's disease in Chinese population. Neurosci Lett.,2009,465 (2):181-183
[77]Ma Z, Han D, Zuo X, Wang F,et al., Association between promoter polymorphisms of the nicastrin gene and sporadic Alzheimer's disease in North Chinese Han population. Neurosci Lett.,2009,458(3):136-139
[78]Wang Y, Jia J. Association between promoter polymorphisms in anterior pharynx-defective-la and sporadic Alzheimer's disease in the North Chinese Han population. Neurosci Lett.,2009,455(2):101-104
[79]Jiang H, Jia J. Association between NR2B subunit gene (GRIN2B) promoter polymorphisms and sporadic Alzheimer's disease in the North Chinese population. Neurosci Lett.,2009,450(3):356-360
[80]Delaere P, Duyckaerts C, He Y, et al., Subtypes and differential laminar distributions of beta A4 deposits in Alzheimer's disease:relationship with the intellectual status of 26 cases. Acta Neuropathol.,1991,81(3):328-335
[81]Fiala JC. Mechanisms of amyloid plaque pathogenesis. Acta Neuropathol., 2007,114(6):551-571
[82]Miyakawa T, Shimoji A, Kuramoto R,et al., The relationship between senile plaques and cerebral blood vessels in Alzheimer's disease and senile dementia. Morphological mechanism of senile plaque production. Virchows Arch B Cell Pathol Incl Mol Pathol.,1982,40(2):121-129
[83]Kawai M, Kalaria RN, Harik SI, et al., The relationship of amyloid plaques to cerebral capillaries in Alzheimer's disease. Am J Pathol.,1990,137(6):1435-1446
[84]Kawai M, Cras P, Perry G. Serial reconstruction of beta-protein amyloid plaques:relationship to microvessels and size distribution. Brain Res.,1992,592 (1-2):278-282
[85]Arriagada PV, Marzloff K, Hyman BT. Distribution of Alzheimer-type pathologic changes in nondemented elderly individuals matches the pattern in Alzheimer's disease. Neurology.,1992,42(9):1681-1688
[86]Price JL, Davis PB, Morris JC, White DL. et al., The distribution of tangles, plaques and related immunohistochemical markers in healthy aging and Alzheimer's disease. Neurobiol Aging.,1991,12(4):295-312
[87]Thal DR, Capetillo-Zarate E, Del Tredici K,et al. Neurodegeneration in normal brain aging and disease. Sci Aging Knowledge Environ.,2004,(23):pe26
[88]Thal DR, et al., Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology.,2002,58(12):1791-1800
[89]Thal DR, Del Tredici K, Braak H.Vascular pathology in Alzheimer disease: correlation of cerebral amyloid angiopathy and arteriosclerosis/lipohyalinosis with cognitive decline. JNeuropathol Exp Neurol.,2003,62(12):1287-1301
[90]Dickstein DL, Walsh J, Brautigam H, et al., Role of vascular risk factors and vascular dysfunction in Alzheimer's disease. Mt Sinai J Med,2010,77(1):82-102
[91]Revesz T, et al., Sporadic and familial cerebral amyloid angiopathies. Brain Pathol.,2002,12(3):343-357
[92]Donahue JE, Flaherty SL, Johanson CE, et al., RAGE, LRP-1, and amyloid-beta protein in Alzheimer's disease. ActaNeuropathol.,2006,112(4):405-415
[93]Kumar-Singh S, Cras P, Wang R,et al., Dense-core senile plaques in the Flemish variant of Alzheimer's disease are vasocentric. Am J Pathol.,2002,161 (2): 507-520
[94]Kumar-Singh S, Pirici D, McGowan E,et al., Dense-core plaques in Tg2576 and PSAPP mouse models of Alzheimer's disease are centered on vessel walls. Am J Pathol.,2005,167(2):527-543
[95]Jeynes B, Provias J. The possible role of capillary cerebral amyloid angiopathy in Alzheimer lesion development:a regional comparison. Acta Neuropathol.,2006,112(4):417-427
[96]Elfenbein HA, Rosen RF, Stephens SL, et al., Cerebral beta-amyloid angiopathy in aged squirrel monkeys. Histol Histopathol.,2007,22(2):155-167
[97]RA., A., Is the clustering of beta-amyloid (A beta) deposits in the frontal cortex of Alzheimer patients determined by blood vessels? Neurosci Lett.,1995,195 (2):121-124
[98]Wisniewski HM, Sadowski M, Jakubowska-Sadowska K, et al., Diffuse, lake-like amyloid-beta deposits in the parvopyramidal layer of the presubiculum in Alzheimer disease. J Neuropathol Exp Neurol.,1998,57(7):674-683
[99]Thal DR, Sassin I, Schultz C, et al., Fleecy amyloid deposits in the internal layers of the human entorhinal cortex are comprised of N-terminal truncated fragments of Abeta. J Neuropathol Exp Neurol.,1999,58(2):210-216
[100]Armstrong RA, Cairns NJ, and L. PL., Are pathological lesions in neurodegenerative disorders the cause or the effect of the degeneration? Neuropathology.,2002,22(3):133-146
[101]RA., A., Size frequency distributions of abnormal protein deposits in Alzheimer's disease and variant Creutzfeldt-Jakob disease. Folia Neuropathol.,2007, 45(3):108-114
[102]Armstrong RA, et al. Size frequency distribution of prion protein (PrP) aggregates in variant Creutzfeldt-Jakob disease (vCJD). J Neural Transm.,2005, 112(1):1565-1573
[103]Armstrong RA, Cairns NJ, and I. JW., Size frequency distributions of the florid prion protein aggregates in variant Creutzfeldt-Jakob disease follow a power-law function. Neurol Sci.,2006,27(2):104-109
[104]Yilmaz E, Ozguc M, Coskun T, et al. Prenatal diagnosis of cystic fibrosis in a Turkish family. Turk J Pediatr.,1991,33(2):79-84
[105]Ganowiak K, Hultman P, Engstrom U, et al., Fibrils from synthetic amyloid-related peptides enhance development of experimental AA-amyloidosis in mice. Biochem Biophys Res Commun.,1994,199(1):306-312
[106]Walker LC, Bian F, Callahan MJ, et al., Modeling Alzheimer's disease and other proteopathies in vivo:is seeding the key? Amino Acids.,2002,23(1-3):87-93
[107]Meyer-Luehmann M, Coomaraswamy J, Bolmont T, et al., Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Science., 2006,313(5794):1781-1784
[108]Eisele YS, Bolmont T, Heikenwalder M, et al., Induction of cerebral beta-amyloidosis:intracerebral versus systemic Abeta inoculation. Proc Natl Acad Sci U S A.,2009,106(31):12926-12931
[109]Arendt T. Alzheimer's disease as a disorder of dynamic brain self-organization. Prog Brain Res.,2005,147:355-378
[110]Gouras GK, Almeida CG, Takahashi RH. Intraneuronal Abeta accumulation and origin of plaques in Alzheimer's disease. Neurobiol Aging.,2005,26(9):1235-1244
[111]Zhao J, Fu Y, Yasvoina M,et al. Beta-site amyloid precursor protein cleaving enzyme 1 levels become elevated in neurons around amyloid plaques: implications for Alzheimer's disease pathogenesis. J Neurosci.,2007,27(14): 3639-3649
[112]Zhang XM, Cai Y, Xiong K, et al. Beta-secretase-1 elevation in transgenic mouse models of Alzheimer's disease is associated with synaptic/axonal pathology and amyloidogenesis:implications for neuritic plaque development. Eur J Neurosci., 2009,30(12):2271-2283
[113]Zhang XM, Xiong K, Cai Y, et al. Functional deprivation promotes amyloid plaque pathogenesis in Tg2576 mouse olfactory bulb and piriform cortex. Eur J Neurosci.,2010,31(4):710-721
[114]Terai K, Iwai A, Kawabata S, et al., Apolipoprotein E deposition and astrogliosis are associated with maturation of beta-amyloid plaques in betaAPPswe transgenic mouse:Implications for the pathogenesis of Alzheimer's disease. Brain Res.,2001,900(1):48-56
[115]van Groen T, Liu L, Ikonen S, et al., Diffuse amyloid deposition, but not plaque number, is reduced in amyloid precursor protein/presenilin 1 double-transgenic mice by pathway lesions. Neuroscience.,2003,119(4):1185-1197
[116]Christie RH, et al. Growth arrest of individual senile plaques in a model of Alzheimer's disease observed by in vivo multiphoton microscopy. J Neurosci., 2001,21(3):858-864
[117]Christie RH, Bacskai BJ, Zipfel WR, et al. Aggregation and disaggregation of senile plaques in Alzheimer disease. Proc Natl Acad Sci U S A.,1997,94(14):7612-7616
[118]叶伟,刘建武,周江宁,等.老年性痴呆症脑内老年斑三维重构及其结构特征分析.科学通报,2005,50(8)：778-782
[119]Golde TE. Alzheimer disease therapy:can the amyloid cascade be halted? JClinInvest.,2003,111(1):11-18
[120]Walsh DM, Selkoe DJ. Deciphering the molecular basis of memory failure in Alzheimer's disease. Neuron.,2004,44(1):181-193
[121]Lemere CA, Masliah E. Can Alzheimer disease be prevented by amyloid-beta immunotherapy? Nat Rev Neurol.,2010,6(2):108-119
[122]Etcheberrigaray R, Tan M, Dewachter I, Kuiperi C, et al. Therapeutic effects of PKC activators in Alzheimer's disease transgenic mice. Proc Natl Acad Sci U S A.,2004,101(30):1 1141-11146
[123]Laird FM, Cai H, Savonenko AV, et al. BACE-1, a major determinant of selective vulnerability of the brain to amyloid-beta amyloidogenesis, is essential for cognitive, emotional, and synaptic functions. J Neurosci.,2005,25(50):1 1693-11709
[124]Ohno M, Sametsky EA, Younkin LH,et al. BACE-1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer's disease. Neuron,2004,41(1):27-33
[125]Hu X, Hicks CW, He W, et al. BACE-1 modulates myelination in the central and peripheral nervous system. Nat Neurosci.,2006,9(12):1520-1525
[126]Savonenko AV, Melnikova T, Laird FM,et al. Alteration of BACE-1-dependent NRGl/ErbB4 signaling and schizophrenia-like phenotypes in BACE-1-null mice. Proc Natl Acad Sci U S A.,2008,105(14):5585-5590
[127]Willem M, Garratt AN, Novak B,et al. Control of peripheral nerve myelination by the beta-secretase BACE-1. Science,2006,314(5799):664-666
[128]Serneels L, Van Biervliet J, Craessaerts K,et al. gamma-Secretase heterogeneity in the Aphl subunit:relevance for Alzheimer's disease. Science,2009, 324(5927):639-642
[129]Li T, Wen H, Brayton C,et al. Moderate reduction of gamma-secretase attenuates amyloid burden and limits mechanism-based liabilities. J Neurosc.,2007, 27(40):10849-10859
[130]Wong GT, et al. Chronic treatment with the gamma-secretase inhibitor LY-411,575 inhibits beta-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J Biol Chem.,2004,279(13):12876-12882
[131]Barten DM, et al. Dynamics of{beta}-amyloid reductions in brain, cerebrospinal fluid, and plasma of{beta}-amyloid precursor protein transgenic mice treated with a{gamma}-secretase inhibitor. J Pharmacol Exp Ther.,2005,312 (2): 635-643
[132]Li T, Wen H, Brayton C,et al. Epidermal growth factor receptor and notch pathways participate in the tumor suppressor function of gamma-secretase. J Biol Chem.,2007,282(44):2264-32273
[133]Thamlikitkul V, Wasuwat S, and K. P., Efficacy of Phyllanthus amarus for eradication of hepatitis B virus in chronic carriers. J Med Assoc Thai.,1991,74(9): 381-385
[134]He G, et al. Gamma-secretase activating protein is a therapeutic target for Alzheimer's disease. Nature,2010,467(7311):95-98
[135]Chow VW, Savonenko AV, Melnikova T,et al. Modeling an anti-amyloid combination therapy for Alzheimer's disease. Sci Transl Med.,2010,2(13):13ral.
[136]McConlogue L, Buttini M, Anderson JP,et al., Partial reduction of BACE-1 has dramatic effects on Alzheimer plaque and synaptic pathology in APP Transgenic Mice. J Biol Chem.,2007,282(36):26326-26334
[137]Dejaegere T, Serneels L, Schafer MK,et al. Deficiency of AphlB/C-gamma-secretase disturbs Nrgl cleavage and sensorimotor gating that can be reversed with antipsychotic treatment. Proc Natl Acad Sci U S A.,2008,105 (28): 9775-9780
[138]Jankowsky JL, Slunt HH, Gonzales V,et al. Persistent amyloidosis following suppression of Abeta production in a transgenic model of Alzheimer disease. PLoS Med.,2005,2(12):e355.
[139]Huang X, Cuajungco MP, Atwood CS,et al. Cu(Ⅱ) potentiation of alzheimer abeta neurotoxicity. Correlation with cell-free hydrogen peroxide production and metal reduction. J Biol Chem.,1999,274(52):37111-37116
[140]Cherny RA, Atwood CS, Xilinas ME,et al. Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer's disease transgenic mice. Neuron,2001,30(3):665-676
[141]Aisen PS, Gauthier S, Vellas B,et al. Alzhemed:a potential treatment for Alzheimer's disease. Curr Alzheimer Res.,2007,4(4):473-478
[142]Gervais F, Paquette J, Morissette C,et al. Targeting soluble Abeta peptide with Tramiprosate for the treatment of brain amyloidosis. Neurobiol Agin.,2007,28 (4):537-547
[143]Santa-Maria I, Hernandez F, Del Rio J,et al. Tramiprosate, a drug of potential interest for the treatment of Alzheimer's disease, promotes an abnormal aggregation of tau. Mol Neurodegener,2007,2:17
[144]Solomon B, Koppel R, Hanan E,et al. Monoclonal antibodies inhibit in vitro fibrillar aggregation of the Alzheimer beta-amyloid peptide. Proc Natl Acad Sci USA.,1996,93(1):452-455
[145]Solomon B, Koppel R, Frankel D,et al. Disaggregation of Alzheimer beta-amyloid by site-directed mAb. Proc Natl Acad Sci U S A.,1997,94(8):4109-4112
[146]Schenk D, Barbour R, Dunn W, et al. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature,1999,400 (6740):173-177
[147]Das P, Murphy MP, Younkin LH, et al., Reduced effectiveness of Abetal-42 immunization in APP transgenic mice with significant amyloid deposition. Neurobiol Aging.,2001,22(5):721-727
[148]Maier M, Seabrook TJ, Lazo ND,et al., Short amyloid-beta (Abeta) immunogens reduce cerebral Abeta load and learning deficits in an Alzheimer's disease mouse model in the absence of an Abeta-specific cellular immune response. J Neurosci.,2006,26(1 8):4717-4728
[149]Janus C, Pearson J, McLaurin J,et al., A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease. Nature,2000, 408(6815):979-982
[150]Morgan D, Diamond DM, Gottschall PE,et al., A beta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease. Nature,2000, 408(6815):982-985.
[151]DeMattos RB, Bales KR, Cummins DJ,et al. Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A.,2001,98 (15): 8850-8855