國立臺灣師範大學博碩士論文全文系統

簡易檢索 / 詳目顯示

回結果列表

研究生：	黃慧貞 Hei-Jen Huang
論文名稱：	環境因子與Abeta1-40加成性傷害空間學習及記憶行為 The synergistic effects of environmental factors and Abeta1-40 impaired the spatial learning and memory in mice
指導教授：	謝秀梅 Hsieh, Hsiu-Mei
學位類別：	博士 Doctor
系所名稱：	生命科學系 Department of Life Science
論文出版年：	2010
畢業學年度：	98
語文別：	英文
論文頁數：	97
中文關鍵詞：	阿茲海默氏症、壓力、老化、高血糖、抗氧化治療、Aβ1-40蛋白質
英文關鍵詞：	Alzheimer’s disease, stress, aging, hyperglycemia, antioxidant therapy, Aβ1-40
論文種類：	學術論文
相關次數：	點閱：190 下載：5
分享至:	分享至facebook 分享至twitter

查詢本校圖書館目錄查詢臺灣博碩士論文知識加值系統勘誤回報

阿茲海默氏症(Alzheimer's Disease)於中樞神經系統內主要病變特徵之一為澱粉樣斑塊堆積。Aβ蛋白質（長約39到43個胺基酸）是穿膜本體蛋白質β-amyloid precursor protein (APP)的代謝物，是造成澱粉樣斑塊最主要之原因；大部分Aβ蛋白質為Aβ1-40與Aβ1-42。雖然Aβ1-42於澱粉樣斑塊及認知功能受損中扮演著舉足輕重的角色，但是在阿茲海默氏症早期階段時Aβ1-40的分泌量遠超過Aβ1-42；甚至有研究發現Aβ1-40在阿茲海默氏症晚期階段病因形成有所相關。因此本論文主要探討環境因子是否會提升Aβ1-40的毒性及如何造成神經退化之機轉。首先，第一個實驗所運用的環境因子為第I型糖尿病所造成的高血糖與Aβ1-40交互作用所產生的影響。結果發現，單獨高血糖或Aβ1-40都無法造成海馬回顯著性地神經退化及空間學習及記憶之損壞；但是高血糖同時併入Aβ1-40會造成Aβ1-40大量堆積、氧化壓力增加及細胞凋亡，最後導致空間學習及記憶之受損。第二個實驗主要探討老化(aged)與Aβ1-40之間的關係，所使用的老鼠為阿茲海默氏症雙基因 (APP/PS1) 突變的背景鼠種(C57BL/6J × C3H)。雖然不論何種阿茲海默氏症基因轉殖鼠均無法完全模擬人類罹患阿茲海默氏症，然而不同鼠種背景之阿茲海默氏症基因轉殖鼠其致病原因及行為受損程度卻有所差異。因為我們實驗室APP/PS1雙基因突變的基因轉殖鼠其背景鼠種為(C57BL/6J × C3H)，所以此實驗對象為C57BL/6J (母) 與 C3H (公) 交配所產生的第一子代公鼠。結果發現，老化與Aβ1-40交互作用會產生短暫性體重下降及空間記憶提取之問題；所以推測體重短暫性下降或許是老年癡呆症的早期訊號。最後一個實驗探討之環境因子是目前時下許多人所面臨之狀況—壓力，觀察壓力與Aβ1-40之間的交互作用；結果發現海馬回處出現細胞凋亡及突觸功能受損而導致嚴重的空間學習及記憶之受損。綜合以上的結果，發現Aβ1-40的毒性會受到環境因子之影響而提升而且不論哪一種環境因子與Aβ1-40相互作用都是透過氧化壓力之傷害，因此建議抗氧化壓力之治療或預防措施能延緩阿茲海默氏症病程之發展。

The deposition of beta amyloid (Aβ) as soluble or insoluble aggregates in senile plaques has been well characterized in the Alzheimer’s disease (AD) brain. Aβ peptides are composed of 39-43 amino acids derived from the soluble metabolic products of amyloid beta precursor protein (APP). Most of the soluble Aβ species comprise the species Aβ1-40 and Aβ1-42. Many studies focus on the Aβ1-42, which plays an important role in plaques and behavioral deficits in the AD. However, Aβ1-40 receives more attention in recent AD studies. A higher proportion of Aβ1-40 is present in the brain under the general condition, an increase of Aβ1-40 / Aβ1-42 ratio in cerebrospinal fluid was identified at the early stage of AD, and an important role of Aβ1-40 was identified in the pathogenesis of late-onset sporadic AD. Therefore, this dissertation worked on characterization of the effects of the interaction between environmental factors and Aβ1-40. First, we found that the neurotoxicity of Aβ1-40 could be enhanced by hyperglycemia, that enhanced the AD symptoms through the oxidative stress caused by Aβ accumulation. Second, the interaction between Aβ1-40 infusion and aged not only caused transient body-weight loss but also impaired the retrieval of spatial reference memory in the C57BL/6J × C3H hybrid mice which have been used as the common AD transgenic model, the APP/PS1 double mutant mice. Therefore, transient body-weight loss may be an important sign of early dementia with aging. Finally, the combined treatment of the stress and oligomer Aβ1-40 induced severe impairment of spatial learning and memory through apoptosis and synaptic dysfunction in the hippocampus. The above results, we suggested that the interaction between Aβ1-40 and environmental factors induced the cognitive dysfunction through the oxidative stress. Therefore, the antioxidant therapy may be a potential strategy to delay the onset of these devastating pathologies.

CHAPTER 1 Introduction    1
1.1 Characterization and classification of Alzheimer’s disease    1
1.2 Modification of amyloid cascade hypothesis    2
1.3 Nontransgenic as exogenous amyloid model versus the transgenic model of ADs    3
1.4 Aβ1-40 versus Aβ1-42    5

CHAPTER 2 Intrahippocampal administration of Aβ1–40 impairs spatial learning and memory in hyperglycemic mice    9
Abstract    9
2.1 Introduction    10
2.2 Material and methods    12
2.2.1 Animals    12
2.2.2 Experimental timeline    12
2.2.3 Hyperglycemia procedure    13
2.2.4 Preparation of oligomer and monomer Aβ1–40    13
2.2.5 Animal surgery    14
2.2.6 Morris water maze (MWM)    14
2.2.7 Histology and immunohistochemistry    16
2.2.8 Statistical analysis    17
2.3 Results and discussion    18
2.3.1 Hyperglycemia was induced by the STZ    18
2.3.2 Impaired spatial reference learning and memory of oligomer Aβ1–40-treated hyperglycemic mice    18
2.3.3 Increasing Aβ accumulation, apoptotic signal, and oxidative stress in the CA1 regions of hyperglycemic mice injected with oligomer Aβ1–40    21

CHAPTER 3 Continuous Aβ1-40 infusion affects the retrieval of spatial reference memory and body weight in C57BL/6J × C3H hybrid aging mice     34
Abstract    34
3.1 Introduction    34
3.1.1 The role of the Aβ1-40 in AD    34
3.1.2 Aging in C57BL/6J × C3H hybrid mice    35
3.2 Methods    36
3.2.1 Subjects    36
3.2.2 Procedures    36
3.2.3 Morris water maze (MWM)    37
3.2.4 Immunohistochemistry    37
3.2.5 Statistical analysis    38
3.3 Results    38
3.3.1 Transient body weight loss accompanied with apoptosis of the LH region in aging treated Aβ1-40 mice    38
3.3.2 Impairment of spatial memory    39
3.4 Discussion    40
3.5 Conclusion    43

CHAPTER 4 The interaction between acute oligomer Aβ1-40 and stress severely impaired the spatial learning and memory     51
Abstract    51
4.1 Introduction    52
4.1.1 The role of stress in AD    52
4.1.2 Hippocampus    53
4.2 Materials and methods    54
4.2.1 Subjects    54
4.2.2 Experiment timeline and establishment of the stress model    55
4.2.3 Analysis of corticosterone level    56
4.2.4 Preparation of oligomer    56
4.2.5 Animal surgery    56
4.2.6 Locomotor    57
4.2.7 Light-dark transition test    57
4.2.8 Morris water maze (MWM)    58
4.2.9 Immunohistochemistry    58
4.2.10 Western blot analysis    59
4.2.11 Data analysis    60
4.3 Results    60
4.3.1 Stress enhanced the plasma corticosterone level of treated animals    60
4.3.2 The avoidance into the dark compartment was increased with aversive experience in stress mice    61
4.3.3 Motor activity was not affected in stress mice regardless of oligomer  Aβ1-40 or vehicle treatment    61
4.3.4 Alteration of cholinergic, noradrenergic, and serotonergic immunoreactive neurons in stress and oligomer Aβ1-40 treated animals    62
4.3.5 Increasing Aβ accumulation, oxidative stress, and apoptotic signal in the stress and oligomer Aβ1–40 treated mice    63
4.3.6 Reduction of calbindin immunoreactive neurons in stress and oligomer Aβ1-40 treated mice    64
4.3.7 Increases in the GR/MR ratio and CRF-1 expression, and decreases in NF-κB and NR 2A/2B expression were observed in the hippocampus of the combined stress and oligomer Aβ1-40-treated mice    64
4.3.8 Spatial reference learning and memory was severely impaired in stress and oligomer Aβ1-40 treated mice    64
4.4 Discussion    66

CHAPTER 5 Conclusions and future prospect     81
5.1 The impacts of environmental factors on Aβ1-40    81
5.2 The potential of antioxidant therapy in AD    81
5.3 The future prospect in AD    81

References     83
Autobiographical statement     96


LIST OF TABLES
Table 1 Body weight measurements, Aβ deposition, oxidative stress, and apoptosis of the different treatment group    44
Table 2 The quantification of the immunohistochemical analyses in the different treatment mice    71

LIST OF FIGURES
Figure 1 Senile plaque and neurofibrillary tangle    7
Figure 2 Amyloid cascade hypothesis    8
Figure 3 Hyperglycemia of C57BL/6J male mice induced by STZ treatment    26
Figure 4 Effect of Aβ1–40 peptide on performance of water maze task    27
Figure 5 The Aβ1–40 injection sites confirmed by cresyl violet staining    30
Figure 6 Immunohistochemistry of Aβ1–40 deposition in the CA1 region of hippocampus    31
Figure 7 Results of caspase-3 signal showing apoptosis in the subregions of the mouse hippocampus    32
Figure 8 Results of MnSOD staining showing oxidative stress occurred in mouse brains    33
Figure 9 Effects of Aβ1–40 on mouse performance during a water maze task    45
Figure 10 Reduction of cholinergic, noradrenergic, and calbindin immunoreactive neurons in treated mice    49
Figure 11 The experimental timeline of this study    72
Figure 12 Plasma corticosterone levels in stress and nonstress mice    73
Figure 13 Anxiety evaluation of stress and nonstress mice after acute CA1 administration with oligomer Aβ1–40 and vehicle    74
Figure 14 The interactive effects of oligomer Aβ1–40 and stress on the motor activity of mice    75
Figure 15 Reduction of cholinergic, noradrenergic, and serotonergic immunoreacitve neurons in treated mice    76
Figure 16 Immunohistochemistry of Aβ1–40 accumulation, oxidative stress and apoptosis in treated mice    77
Figure 17 Calbindin expression in the CA1 subregion of hippocampus in treated mice    78
Figure 18 GR/MR ratio, CRF-1, NF-κB and NR2A/2B expressions in hippocampus of the treated mice    79
Figure 19 Interactive effects of oligmer Aβ1–40 peptide and stress on mouse performance during a water maze task    80

Figure 20 The diagram showing the interaction between Aβ1-40 and environmental factors and resulting cognitive dysfunction by oxidative stress     82

SUPPLEMENTAL DATA
(A)Experimental timeline of examining the role of the Aβ1–40 in different age hybrid mice    50
(B)The structure of Aβ1–40 after incubation at 37℃ for 7 days and 14 days    50
                                

1. Blacker D, Wilcox MA, Laird NM, et al. Alpha-2 macroglobulin is genetically associated with Alzheimer disease. Nat Genet 1998;19:357-360
2. Lehmann DJ, Johnston C, Smith AD. Synergy between the genes for butyrylcholinesterase K variant and apolipoprotein E4 in late-onset confirmed Alzheimer's disease. Hum Mol Genet 1997;6:1933-1936
3. Law A, Gauthier S, Quirion R. Say NO to Alzheimer's disease: the putative links between nitric oxide and dementia of the Alzheimer's type. Brain Res Brain Res Rev 2001;35:73-96
4. Selkoe DJ, Schenk D. Alzheimer's disease: molecular understanding predicts amyloid-based therapeutics. Annu Rev Pharmacol Toxicol 2003;43:545-584
5. Golde TE. Alzheimer disease therapy: can the amyloid cascade be halted? J Clin Invest 2003;111:11-18
6. Glenner GG, Wong CW. Alzheimer's disease and Down's syndrome: sharing of a unique cerebrovascular amyloid fibril protein. Biochem Biophys Res Commun 1984;122:1131-1135
7. Lustbader JW, Cirilli M, Lin C, et al. ABAD directly links Abeta to mitochondrial toxicity in Alzheimer's disease. Science 2004;304:448-452
8. Xie L, Helmerhorst E, Taddei K, et al. Alzheimer's beta-amyloid peptides compete for insulin binding to the insulin receptor. J Neurosci 2002;22:RC221
9. Billings LM, Oddo S, Green KN, McGaugh JL, LaFerla FM. Intraneuronal Abeta causes the onset of early Alzheimer's disease-related cognitive deficits in transgenic mice. Neuron 2005;45:675-688
10. Bloom GS, Ren K, Glabe CG. Cultured cell and transgenic mouse models for tau pathology linked to beta-amyloid. Biochim Biophys Acta 2005;1739:116-124
11. Walsh DM, Klyubin I, Fadeeva JV, et al. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 2002;416:535-539
12. Stephan A, Phillips AG. A case for a non-transgenic animal model of Alzheimer's disease. Genes Brain Behav 2005;4:157-172
13. Reynolds A, Laurie C, Mosley RL, Gendelman HE. Oxidative stress and the pathogenesis of neurodegenerative disorders. Int Rev Neurobiol 2007;82:297-325
14. Tripathy D, Grammas P. Acetaminophen inhibits neuronal inflammation and protects neurons from oxidative stress. J Neuroinflammation 2009;6:10
15. Wong CH, Crack PJ. Modulation of neuro-inflammation and vascular response by oxidative stress following cerebral ischemia-reperfusion injury. Curr Med Chem 2008;15:1-14
16. Holcomb L, Gordon MN, McGowan E, et al. Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat Med 1998;4:97-100
17. Hsiao KK, Borchelt DR, Olson K, et al. Age-related CNS disorder and early death in transgenic FVB/N mice overexpressing Alzheimer amyloid precursor proteins. Neuron 1995;15:1203-1218
18. Irizarry MC, Soriano F, McNamara M, et al. Abeta deposition is associated with neuropil changes, but not with overt neuronal loss in the human amyloid precursor protein V717F (PDAPP) transgenic mouse. J Neurosci 1997;17:7053-7059
19. Games D, Adams D, Alessandrini R, et al. Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature 1995;373:523-527
20. Clemens JA, Stephenson DT. Implants containing beta-amyloid protein are not neurotoxic to young and old rat brain. Neurobiol Aging 1992;13:581-586
21. Podlisny MB, Stephenson DT, Frosch MP, et al. Microinjection of synthetic amyloid beta-protein in monkey cerebral cortex fails to produce acute neurotoxicity. Am J Pathol 1993;142:17-24
22. Koo EH, Park L, Selkoe DJ. Amyloid beta-protein as a substrate interacts with extracellular matrix to promote neurite outgrowth. Proc Natl Acad Sci U S A 1993;90:4748-4752
23. Yankner BA, Benowitz LI, Villa-Komaroff L, Neve RL. Transfection of PC12 cells with the human GAP-43 gene: effects on neurite outgrowth and regeneration. Brain Res Mol Brain Res 1990;7:39-44
24. Einstein G, Buranosky R, Crain BJ. Dendritic pathology of granule cells in Alzheimer's disease is unrelated to neuritic plaques. J Neurosci 1994;14:5077-5088
25. Gearing M, Wilson RW, Unger ER, et al. Amyloid precursor protein (APP) in the striatum in Alzheimer's disease: an immunohistochemical study. J Neuropathol Exp Neurol 1993;52:22-30
26. Cochran E, Bacci B, Chen Y, et al. Amyloid precursor protein and ubiquitin immunoreactivity in dystrophic axons is not unique to Alzheimer's disease. Am J Pathol 1991;139:485-489
27. Dodart JC, Mathis C, Bales KR, Paul SM. Does my mouse have Alzheimer's disease? Genes Brain Behav 2002;1:142-155
28. Higgins GA, Jacobsen H. Transgenic mouse models of Alzheimer's disease: phenotype and application. Behav Pharmacol 2003;14:419-438
29. Oddo S, Caccamo A, Shepherd JD, et al. Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 2003;39:409-421
30. King DL, Arendash GW. Behavioral characterization of the Tg2576 transgenic model of Alzheimer's disease through 19 months. Physiol Behav 2002;75:627-642
31. Calhoun ME, Burgermeister P, Phinney AL, et al. Neuronal overexpression of mutant amyloid precursor protein results in prominent deposition of cerebrovascular amyloid. Proc Natl Acad Sci U S A 1999;96:14088-14093
32. Whitehead SN, Cheng G, Hachinski VC, Cechetto DF. Progressive increase in infarct size, neuroinflammation, and cognitive deficits in the presence of high levels of amyloid. Stroke 2007;38:3245-3250
33. Whitehead SN, Hachinski VC, Cechetto DF. Interaction between a rat model of cerebral ischemia and beta-amyloid toxicity: inflammatory responses. Stroke 2005;36:107-112
34. Selkoe DJ. Alzheimer's disease: genes, proteins, and therapy. Physiol Rev 2001;81:741-766
35. Younkin SG. Evidence that A beta 42 is the real culprit in Alzheimer's disease. Ann Neurol 1995;37:287-288
36. Shiwany NA, Xie J, Guo Q. Cortical Neurons Transgenic for Human Abeta40 or Abeta42 Have Similar Vulnerability to Apoptosis despite Their Different Amyloidogenic Properties. Int J Clin Exp Pathol 2009;2:339-352
37. Selkoe DJ. The molecular pathology of Alzheimer's disease. Neuron 1991;6:487-498
38. Ball MJ, Fisman M, Hachinski V, et al. A new definition of Alzheimer's disease: a hippocampal dementia. Lancet 1985;1:14-16
39. Duyckaerts C, Uchihara T, Seilhean D, He Y, Hauw JJ. Dissociation of Alzheimer type pathology in a disconnected piece of cortex. Acta Neuropathol 1997;93:501-507
40. Hyman BT, Van Hoesen GW, Damasio AR, Barnes CL. Alzheimer's disease: cell-specific pathology isolates the hippocampal formation. Science 1984;225:1168-1170
41. Hyman BT, Van Hoesen GW, Kromer LJ, Damasio AR. Perforant pathway changes and the memory impairment of Alzheimer's disease. Ann Neurol 1986;20:472-481
42. Squire LR. Mechanisms of memory. Science 1986;232:1612-1619
43. Wallenstein GV, Eichenbaum H, Hasselmo ME. The hippocampus as an associator of discontiguous events. Trends Neurosci 1998;21:317-323
44. Chen G, Chen KS, Knox J, et al. A learning deficit related to age and beta-amyloid plaques in a mouse model of Alzheimer's disease. Nature 2000;408:975-979
45. Gordon MN, King DL, Diamond DM, et al. Correlation between cognitive deficits and Abeta deposits in transgenic APP+PS1 mice. Neurobiol Aging 2001;22:377-385
46. 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;408:979-982
47. 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;408:982-985
48. Kawarabayashi T, Younkin LH, Saido TC, et al. Age-dependent changes in brain, CSF, and plasma amyloid (beta) protein in the Tg2576 transgenic mouse model of Alzheimer's disease. J Neurosci 2001;21:372-381
49. Dahlgren KN, Manelli AM, Stine WB, Jr., et al. Oligomeric and fibrillar species of amyloid-beta peptides differentially affect neuronal viability. J Biol Chem 2002;277:32046-32053
50. Kayed R, Head E, Thompson JL, et al. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 2003;300:486-489
51. Stefani M, Dobson CM. Protein aggregation and aggregate toxicity: new insights into protein folding, misfolding diseases and biological evolution. J Mol Med 2003;81:678-699
52. Walsh DM, Hartley DM, Kusumoto Y, et al. Amyloid beta-protein fibrillogenesis. Structure and biological activity of protofibrillar intermediates. J Biol Chem 1999;274:25945-25952
53. Butterfield DA, Drake J, Pocernich C, Castegna A. Evidence of oxidative damage in Alzheimer's disease brain: central role for amyloid beta-peptide. Trends Mol Med 2001;7:548-554
54. Eckert A, Keil U, Marques CA, et al. Mitochondrial dysfunction, apoptotic cell death, and Alzheimer's disease. Biochem Pharmacol 2003;66:1627-1634
55. Lashuel HA, Hartley D, Petre BM, Walz T, Lansbury PT, Jr. Neurodegenerative disease: amyloid pores from pathogenic mutations. Nature 2002;418:291
56. Lue LF, Kuo YM, Roher AE, et al. Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer's disease. Am J Pathol 1999;155:853-862
57. Mattson MP, Cheng B, Davis D, et al. beta-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity. J Neurosci 1992;12:376-389
58. Awad N, Gagnon M, Messier C. The relationship between impaired glucose tolerance, type 2 diabetes, and cognitive function. J Clin Exp Neuropsychol 2004;26:1044-1080
59. Gispen WH, Biessels GJ. Cognition and synaptic plasticity in diabetes mellitus. Trends Neurosci 2000;23:542-549
60. Cardinal JW, Margison GP, Mynett KJ, et al. Increased susceptibility to streptozotocin-induced beta-cell apoptosis and delayed autoimmune diabetes in alkylpurine-DNA-N-glycosylase-deficient mice. Mol Cell Biol 2001;21:5605-5613
61. Sigaudo-Roussel D, Demiot C, Fromy B, et al. Early endothelial dysfunction severely impairs skin blood flow response to local pressure application in streptozotocin-induced diabetic mice. Diabetes 2004;53:1564-1569
62. Smyth MD, Kesslak JP, Cummings BJ, Cotman CW. Analysis of brain injury following intrahippocampal administration of beta-amyloid in streptozotocin-treated rats. Neurobiol Aging 1994;15:153-159
63. Finkel T, Holbrook NJ. Oxidants, oxidative stress and the biology of ageing. Nature 2000;408:239-247
64. Zhang Y, Herman B. Apoptosis and successful aging. Mech Ageing Dev 2002;123:563-565
65. Hoshi M, Sato M, Matsumoto S, et al. Spherical aggregates of beta-amyloid (amylospheroid) show high neurotoxicity and activate tau protein kinase I/glycogen synthase kinase-3beta. Proc Natl Acad Sci U S A 2003;100:6370-6375
66. Janus C, Westaway D. Transgenic mouse models of Alzheimer's disease. Physiol Behav 2001;73:873-886
67. Buchsbaum MS, Kesslak JP, Lynch G, et al. Temporal and hippocampal metabolic rate during an olfactory memory task assessed by positron emission tomography in patients with dementia of the Alzheimer type and controls. Preliminary studies. Arch Gen Psychiatry 1991;48:840-847
68. Duara R, Grady C, Haxby J, et al. Positron emission tomography in Alzheimer's disease. Neurology 1986;36:879-887
69. Broe GA, Henderson AS, Creasey H, et al. A case-control study of Alzheimer's disease in Australia. Neurology 1990;40:1698-1707
70. Henderson AS. The risk factors for Alzheimer's disease: a review and a hypothesis. Acta Psychiatr Scand 1988;78:257-275
71. Chapman PF, White GL, Jones MW, et al. Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice. Nat Neurosci 1999;2:271-276
72. Townsend M, Shankar GM, Mehta T, Walsh DM, Selkoe DJ. Effects of secreted oligomers of amyloid beta-protein on hippocampal synaptic plasticity: a potent role for trimers. J Physiol 2006;572:477-492
73. Ishibashi K, Tomiyama T, Nishitsuji K, Hara M, Mori H. Absence of synaptophysin near cortical neurons containing oligomer Abeta in Alzheimer's disease brain. J Neurosci Res 2006;84:632-636
74. Biessels GJ, Kappelle LJ. Increased risk of Alzheimer's disease in Type II diabetes: insulin resistance of the brain or insulin-induced amyloid pathology? Biochem Soc Trans 2005;33:1041-1044
75. Kamal A, Biessels GJ, Duis SE, Gispen WH. Learning and hippocampal synaptic plasticity in streptozotocin-diabetic rats: interaction of diabetes and ageing. Diabetologia 2000;43:500-506
76. Yagihashi S, Yamagishi SI, Wada Ri R, et al. Neuropathy in diabetic mice overexpressing human aldose reductase and effects of aldose reductase inhibitor. Brain 2001;124:2448-2458
77. Patil CS, Singh VP, Kulkarni SK. Modulatory effect of sildenafil in diabetes and electroconvulsive shock-induced cognitive dysfunction in rats. Pharmacol Rep 2006;58:373-380
78. West MJ, Coleman PD, Flood DG, Troncoso JC. Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer's disease. Lancet 1994;344:769-772
79. Munch G, Schinzel R, Loske C, et al. Alzheimer's disease--synergistic effects of glucose deficit, oxidative stress and advanced glycation endproducts. J Neural Transm 1998;105:439-461
80. Kim HJ, Chae SC, Lee DK, et al. Selective neuronal degeneration induced by soluble oligomeric amyloid beta protein. Faseb J 2003;17:118-120
81. Stadelmann C, Deckwerth TL, Srinivasan A, et al. Activation of caspase-3 in single neurons and autophagic granules of granulovacuolar degeneration in Alzheimer's disease. Evidence for apoptotic cell death. Am J Pathol 1999;155:1459-1466
82. Su JH, Zhao M, Anderson AJ, Srinivasan A, Cotman CW. Activated caspase-3 expression in Alzheimer's and aged control brain: correlation with Alzheimer pathology. Brain Res 2001;898:350-357
83. Butterfield DA, Hensley K, Harris M, Mattson M, Carney J. beta-Amyloid peptide free radical fragments initiate synaptosomal lipoperoxidation in a sequence-specific fashion: implications to Alzheimer's disease. Biochem Biophys Res Commun 1994;200:710-715
84. Auer RN, Siesjo BK. Hypoglycaemia: brain neurochemistry and neuropathology. Baillieres Clin Endocrinol Metab 1993;7:611-625
85. Kishi Y, Nickander KK, Schmelzer JD, Low PA. Gene expression of antioxidant enzymes in experimental diabetic neuropathy. J Peripher Nerv Syst 2000;5:11-18
86. Jarrard LE. The hippocampus and motivation. Psychol Bull 1973;79:1-12
87. Morris RG, Garrud P, Rawlins JN, O'Keefe J. Place navigation impaired in rats with hippocampal lesions. Nature 1982;297:681-683
88. Yin S, Guan Z, Tang Y, et al. Abnormal expression of epilepsy-related gene ERG1/NSF in the spontaneous recurrent seizure rats with spatial learning memory deficits induced by kainic acid. Brain Res 2005;1053:195-202
89. Wilson MA, McNaughton BL. Dynamics of the hippocampal ensemble code for space. Science 1993;261:1055-1058
90. Lothman EW, Bertram EH, 3rd, Stringer JL. Functional anatomy of hippocampal seizures. Prog Neurobiol 1991;37:1-82
91. Volpe BT, Davis HP, Towle A, Dunlap WP. Loss of hippocampal CA1 pyramidal neurons correlates with memory impairment in rats with ischemic or neurotoxin lesions. Behav Neurosci 1992;106:457-464
92. Wood ER, Mumby DG, Pinel JP, Phillips AG. Impaired object recognition memory in rats following ischemia-induced damage to the hippocampus. Behav Neurosci 1993;107:51-62
93. Kalesnykas G, Puolivali J, Sirvio J, Miettinen R. Cholinergic neurons in the basal forebrain of aged female mice. Brain Res 2004;1022:148-156
94. Palop JJ, Jones B, Kekonius L, et al. Neuronal depletion of calcium-dependent proteins in the dentate gyrus is tightly linked to Alzheimer's disease-related cognitive deficits. Proc Natl Acad Sci U S A 2003;100:9572-9577
95. Beach TG. Physiologic origins of age-related beta-amyloid deposition. Neurodegener Dis 2008;5:143-145
96. Oakley H, Cole SL, Logan S, et al. Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formation. J Neurosci 2006;26:10129-10140
97. Kanai M, Matsubara E, Isoe K, et al. Longitudinal study of cerebrospinal fluid levels of tau, A beta1-40, and A beta1-42(43) in Alzheimer's disease: a study in Japan. Ann Neurol 1998;44:17-26
98. Ishii K, Tamaoka A, Mizusawa H, et al. Abeta1-40 but not Abeta1-42 levels in cortex correlate with apolipoprotein E epsilon4 allele dosage in sporadic Alzheimer's disease. Brain Res 1997;748:250-252
99. Huang HJ, Liang KC, Chen CP, Chen CM, Hsieh-Li HM. Intrahippocampal administration of A beta(1-40) impairs spatial learning and memory in hyperglycemic mice. Neurobiol Learn Mem 2007;87:483-494
100. Hu NW, Smith IM, Walsh DM, Rowan MJ. Soluble amyloid-beta peptides potently disrupt hippocampal synaptic plasticity in the absence of cerebrovascular dysfunction in vivo. Brain 2008;131:2414-2424
101. Wahlsten D, Rustay NR, Metten P, Crabbe JC. In search of a better mouse test. Trends Neurosci 2003;26:132-136
102. Borchelt DR, Ratovitski T, van Lare J, et al. Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins. Neuron 1997;19:939-945
103. Wang J, Tanila H, Puolivali J, Kadish I, van Groen T. Gender differences in the amount and deposition of amyloidbeta in APPswe and PS1 double transgenic mice. Neurobiol Dis 2003;14:318-327
104. Alves CJ, Magalhaes A, Summavielle T, et al. Hormonal, neurochemical, and behavioral response to a forced swim test in adolescent rats throughout cocaine withdrawal. Ann N Y Acad Sci 2008;1139:366-373
105. Uecker A, Gonzalez-Lima F, Cada A, Reiman EM. Behavior and brain uptake of fluorodeoxyglucose in mature and aged C57BL/6 mice. Neurobiol Aging 2000;21:705-718
106. Prediger RD, Franco JL, Pandolfo P, et al. Differential susceptibility following beta-amyloid peptide-(1-40) administration in C57BL/6 and Swiss albino mice: Evidence for a dissociation between cognitive deficits and the glutathione system response. Behav Brain Res 2007;177:205-213
107. Leahey TM, Myers TA, Gunstad J, et al. Abeta40 is associated with cognitive function, body fat and physical fitness in healthy older adults. Nutr Neurosci 2007;10:205-209
108. Pugh PL, Richardson JC, Bate ST, Upton N, Sunter D. Non-cognitive behaviours in an APP/PS1 transgenic model of Alzheimer's disease. Behav Brain Res 2007;178:18-28
109. Bucht G, Sandman PO. Nutritional aspects of dementia, especially Alzheimer's disease. Age Ageing 1990;19:S32-36
110. Koistinaho M, Koistinaho J. Interactions between Alzheimer's disease and cerebral ischemia--focus on inflammation. Brain Res Brain Res Rev 2005;48:240-250
111. Veenema AH, Reber SO, Selch S, Obermeier F, Neumann ID. Early life stress enhances the vulnerability to chronic psychosocial stress and experimental colitis in adult mice. Endocrinology 2008;149:2727-2736
112. Weinsier RL, Nagy TR, Hunter GR, et al. Do adaptive changes in metabolic rate favor weight regain in weight-reduced individuals? An examination of the set-point theory. Am J Clin Nutr 2000;72:1088-1094
113. Moser MB, Tollefsrud A, Moser EI, Andersen P. Multiple substrates for spatial learning in the rat hippocampus. Soc Neurosci Abstr 1997;23:621
114. Kubik S, Fenton AA. Behavioral evidence that segregation and representation are dissociable hippocampal functions. J Neurosci 2005;25:9205-9212
115. Hersi AI, Rowe W, Gaudreau P, Quirion R. Dopamine D1 receptor ligands modulate cognitive performance and hippocampal acetylcholine release in memory-impaired aged rats. Neuroscience 1995;69:1067-1074
116. Fujishiro H, Umegaki H, Isojima D, et al. Depletion of cholinergic neurons in the nucleus of the medial septum and the vertical limb of the diagonal band in dementia with Lewy bodies. Acta Neuropathol 2006;111:109-114
117. Wu CW, Yeh HH. Nerve growth factor rapidly increases muscarinic tone in mouse medial septum/diagonal band of Broca. J Neurosci 2005;25:4232-4242
118. Kalinin S, Gavrilyuk V, Polak PE, et al. Noradrenaline deficiency in brain increases beta-amyloid plaque burden in an animal model of Alzheimer's disease. Neurobiol Aging 2007;28:1206-1214
119. Popovic M, Caballero-Bleda M, Kadish I, Van Groen T. Subfield and layer-specific depletion in calbindin-D28K, calretinin and parvalbumin immunoreactivity in the dentate gyrus of amyloid precursor protein/presenilin 1 transgenic mice. Neuroscience 2008;155:182-191
120. Akbari E, Naghdi N, Motamedi F. The selective orexin 1 receptor antagonist SB-334867-A impairs acquisition and consolidation but not retrieval of spatial memory in Morris water maze. Peptides 2007;28:650-656
121. Oomura Y, Aou S, Matsumoto I, Sakata T. Physiological significance of 2-buten-4-olide (2-B4O), an endogenous satiety substance increased in the fasted state. Exp Biol Med (Maywood) 2003;228:1146-1155
122. Eichenbaum H. Declarative memory: insights from cognitive neurobiology. Annu Rev Psychol 1997;48:547-572
123. Hasegawa T. Prolonged stress will induce Alzheimer's disease in elderly people by increased release of homocysteic acid. Med Hypotheses 2007;69:1135-1139
124. Wilson RS, Arnold SE, Schneider JA, et al. Chronic psychological distress and risk of Alzheimer's disease in old age. Neuroepidemiology 2006;27:143-153
125. Dong H, Yuede CM, Yoo HS, et al. Corticosterone and related receptor expression are associated with increased beta-amyloid plaques in isolated Tg2576 mice. Neuroscience 2008;155:154-163
126. Peskind ER, Wilkinson CW, Petrie EC, Schellenberg GD, Raskind MA. Increased CSF cortisol in AD is a function of APOE genotype. Neurology 2001;56:1094-1098
127. Weiner MF, Vobach S, Olsson K, Svetlik D, Risser RC. Cortisol secretion and Alzheimer's disease progression. Biol Psychiatry 1997;42:1030-1038
128. Swaab DF, Bao AM, Lucassen PJ. The stress system in the human brain in depression and neurodegeneration. Ageing Res Rev 2005;4:141-194
129. McDonald RJ, Craig LA, Hong NS. Enhanced cell death in hippocampus and emergence of cognitive impairments following a localized mini-stroke in hippocampus if preceded by a previous episode of acute stress. Eur J Neurosci 2008;27:2197-2209
130. Kang JE, Cirrito JR, Dong H, Csernansky JG, Holtzman DM. Acute stress increases interstitial fluid amyloid-beta via corticotropin-releasing factor and neuronal activity. Proc Natl Acad Sci U S A 2007;104:10673-10678
131. Morra JH, Tu Z, Apostolova LG, et al. Automated mapping of hippocampal atrophy in 1-year repeat MRI data from 490 subjects with Alzheimer's disease, mild cognitive impairment, and elderly controls. Neuroimage 2008
132. Behl C. Effects of glucocorticoids on oxidative stress-induced hippocampal cell death: implications for the pathogenesis of Alzheimer's disease. Exp Gerontol 1998;33:689-696
133. De Kloet ER, Vreugdenhil E, Oitzl MS, Joels M. Brain corticosteroid receptor balance in health and disease. Endocr Rev 1998;19:269-301
134. Matos M, Augusto E, Oliveira CR, Agostinho P. Amyloid-beta peptide decreases glutamate uptake in cultured astrocytes: involvement of oxidative stress and mitogen-activated protein kinase cascades. Neuroscience 2008;156:898-910
135. Rammal H, Bouayed J, Younos C, Soulimani R. Evidence that oxidative stress is linked to anxiety-related behaviour in mice. Brain Behav Immun 2008
136. Li S, Murakami Y, Wang M, Maeda K, Matsumoto K. The effects of chronic valproate and diazepam in a mouse model of posttraumatic stress disorder. Pharmacol Biochem Behav 2006;85:324-331
137. Spink AJ, Tegelenbosch RA, Buma MO, Noldus LP. The EthoVision video tracking system--a tool for behavioral phenotyping of transgenic mice. Physiol Behav 2001;73:731-744
138. Costall B, Jones BJ, Kelly ME, Naylor RJ, Tomkins DM. Exploration of mice in a black and white test box: validation as a model of anxiety. Pharmacol Biochem Behav 1989;32:777-785
139. Bland ST, Schmid MJ, Der-Avakian A, et al. Expression of c-fos and BDNF mRNA in subregions of the prefrontal cortex of male and female rats after acute uncontrollable stress. Brain Res 2005;1051:90-99
140. Jin XL, Jin WQ, Zhou DH, Li GF, Chi ZQ. [Effects of ohmefentanyl at anesthetic dose on plasma levels of corticosterone, cortisol and antidiuretic hormone in rats]. Yao Xue Xue Bao 1997;32:228-230
141. Louvart H, Maccari S, Lesage J, et al. Effects of a single footshock followed by situational reminders on HPA axis and behaviour in the aversive context in male and female rats. Psychoneuroendocrinology 2006;31:92-99
142. Ottenweller JE, Natelson BH, Pitman DL, Drastal SD. Adrenocortical and behavioral responses to repeated stressors: toward an animal model of chronic stress and stress-related mental illness. Biol Psychiatry 1989;26:829-841
143. Koba T, Kodama Y, Shimizu K, et al. Persistent behavioural changes in rats following inescapable shock stress: a potential model of posttraumatic stress disorder. World J Biol Psychiatry 2001;2:34-37
144. Ladera-Fernandez V. [Post-traumatic amnesia syndrome]. Rev Neurol 2001;32:467-472
145. Pynoos RS, Ritzmann RF, Steinberg AM, Goenjian A, Prisecaru I. A behavioral animal model of posttraumatic stress disorder featuring repeated exposure to situational reminders. Biol Psychiatry 1996;39:129-134
146. Yan JJ, Kim DH, Moon YS, et al. Protection against beta-amyloid peptide-induced memory impairment with long-term administration of extract of Angelica gigas or decursinol in mice. Prog Neuropsychopharmacol Biol Psychiatry 2004;28:25-30
147. Van den Berg CL, Lamberts RR, Wolterink G, Wiegant VM, Van Ree JM. Emotional and footshock stimuli induce differential long-lasting behavioural effects in rats; involvement of opioids. Brain Res 1998;799:6-15
148. van Dijken HH, Mos J, van der Heyden JA, Tilders FJ. Characterization of stress-induced long-term behavioural changes in rats: evidence in favor of anxiety. Physiol Behav 1992;52:945-951
149. Ng F, Berk M, Dean O, Bush AI. Oxidative stress in psychiatric disorders: evidence base and therapeutic implications. Int J Neuropsychopharmacol 2008;11:851-876
150. Zafir A, Banu N. Modulation of in vivo oxidative status by exogenous corticosterone and restraint stress in rats. Stress 2008:1
151. Berridge CW, Waterhouse BD. The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes. Brain Res Brain Res Rev 2003;42:33-84
152. Brand L, Groenewald I, Stein DJ, Wegener G, Harvey BH. Stress and re-stress increases conditioned taste aversion learning in rats: possible frontal cortical and hippocampal muscarinic receptor involvement. Eur J Pharmacol 2008;586:205-211
153. Forster PL, Schoenfeld FB, Marmar CR, Lang AJ. Lithium for irritability in post-traumatic stress disorder. J Trauma Stress 1995;8:143-149
154. Helm KA, Ziegler DR, Gallagher M. Habituation to stress and dexamethasone suppression in rats with selective basal forebrain cholinergic lesions. Hippocampus 2004;14:628-635
155. Keifer J, Brewer BT, Meehan PE, Brue RJ, Clark TG. Role for calbindin-D28K in in vitro classical conditioning of abducens nerve responses in turtles. Synapse 2003;49:106-115
156. Schmid AW LM, Herron CE. The effects of IL-1 receptor antagonist on beta amyloid mediated depression of LTP in the rat CA1 in vivo. Hippocampus 2008
157. Lamour Y, Bassant MH, Potier B, Billard JM, Dutar P. [Aging of memory mechanisms]. C R Seances Soc Biol Fil 1994;188:469-486
158. McIntosh LJ, Hong KE, Sapolsky RM. Glucocorticoids may alter antioxidant enzyme capacity in the brain: baseline studies. Brain Res 1998;791:209-214
159. Hegde P, Singh K, Chaplot S, et al. Stress-induced changes in sleep and associated neuronal activity in rat hippocampus and amygdala. Neuroscience 2008;153:20-30
160. Reagan LP, Grillo CA, Piroli GG. The As and Ds of stress: metabolic, morphological and behavioral consequences. Eur J Pharmacol 2008;585:64-75
161. Tsoory MM, Vouimba RM, Akirav I, et al. Amygdala modulation of memory-related processes in the hippocampus: potential relevance to PTSD. Prog Brain Res 2008;167:35-51
162. Green KN, Billings LM, Roozendaal B, McGaugh JL, LaFerla FM. Glucocorticoids increase amyloid-beta and tau pathology in a mouse model of Alzheimer's disease. J Neurosci 2006;26:9047-9056
163. Lee KW, Kim JB, Seo JS, et al. Behavioral stress accelerates plaque pathogenesis in the brain of Tg2576 mice via generation of metabolic oxidative stress. J Neurochem 2009;108:165-175
164. Misonou H, Morishima-Kawashima M, Ihara Y. Oxidative stress induces intracellular accumulation of amyloid beta-protein (Abeta) in human neuroblastoma cells. Biochemistry 2000;39:6951-6959
165. Shen C, Chen Y, Liu H, et al. Hydrogen peroxide promotes Abeta production through JNK-dependent activation of gamma-secretase. J Biol Chem 2008;283:17721-17730
166. Tabner BJ, El-Agnaf OM, Turnbull S, et al. Hydrogen peroxide is generated during the very early stages of aggregation of the amyloid peptides implicated in Alzheimer disease and familial British dementia. J Biol Chem 2005;280:35789-35792
167. Tamagno E, Parola M, Bardini P, et al. Beta-site APP cleaving enzyme up-regulation induced by 4-hydroxynonenal is mediated by stress-activated protein kinases pathways. J Neurochem 2005;92:628-636
168. Tong Y, Zhou W, Fung V, et al. Oxidative stress potentiates BACE1 gene expression and Abeta generation. J Neural Transm 2005;112:455-469
169. Ji C, Aisa HA, Yang N, et al. Gossypium herbaceam extracts inhibited NF-kappaB activation to attenuate spatial memory impairment and hippocampal neurodegeneration induced by amyloid-beta in rats. J Alzheimers Dis 2008;14:271-283
170. Harvey BH, Oosthuizen F, Brand L, Wegener G, Stein DJ. Stress-restress evokes sustained iNOS activity and altered GABA levels and NMDA receptors in rat hippocampus. Psychopharmacology (Berl) 2004;175:494-502
171. Parameshwaran K, Dhanasekaran M, Suppiramaniam V. Amyloid beta peptides and glutamatergic synaptic dysregulation. Exp Neurol 2008;210:7-13

簡易檢索 / 詳目顯示

相關論文