Tau蛋白过度磷酸化及高脂血症对β淀粉样蛋白生成的影响
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摘要
背景：阿尔茨海默病(AD)是老年人最常见的神经变性疾病。近10年的研究大多数学者支持淀粉样蛋白假说。即：Aβ的异常生成增多，导致了Tau蛋白的异常过度磷酸化，形成了NFTs，继而引起突触功能障碍和神经细胞的调亡。虽然有可能危险因素的持续暴露造成Aβ的产生持续增加，但在AD的病理机制研究中发现不能排除NFTs对Aβ生成有正反馈调节作用。因此Aβ的沉积与NFTs之间的关系不能简单的理解为单向的联系，其中二者之间可能存在有更复杂的关系。因此探明NFTs与β淀粉样蛋白多肽沉积之间的关系将进一步增强对于AD病理基础的认识。同时，胆固醇与AD的关系密切。高胆固醇水平能够促进脑内淀粉样前体蛋白经β分泌酶降解为β淀粉样蛋白，Aβ沉积形成老年斑，同时触发各种免疫反应和神经毒性级联反应，导致广泛的神经元变性，表现为认知障碍。
目的：探讨Tau蛋白过度磷酸化对β淀粉样蛋白蛋白多肽生成是否存在影响。观察高胆固醇血症对淀粉样蛋白生成的影响。
方法：1．用蛋白磷酸酯酶抑制剂冈田酸(OA)在大鼠侧脑室内注射，连续三月。制作Tau蛋白过度磷酸化模型。用Morris水迷宫，免疫组织化学方法观察模型组大鼠行为学改变，及神经原纤维的缠结，淀粉样蛋
Background:
Alzheimer's disease (AD) is a neurodegenerative disorder that is characterized by neuronal loss and the formation of neuritic plaques, neurofibrillary tangles (NFTs), and neuropil threads.In recent 10years,lots of scholars support the hypothesis of amyloidrthe overexpression of Ap can lead to neurofibrillary tangles, further can lead to neuronal apoptosis and synapse disfunction.But we can not deplete the possible that the hyperphosphorylated tau protein can increase the expression of Ap.So the relation of hyperphosphorylated tau protein and Ap may not be simple;The cholesterol, or cholesterol metabolism, plays a role in the pathophysiology of AD. Cholesterol levels can modulate the enzymatic processing of the amyloid precursor protein (APP) and Ap production. Neurotoxic of amyloid can lead to neuronal apoptosis and show dementia in clinical.
Objective:
To explore the effect of hyperphosphorylated tau protein and hypercholesteremia on the expression of β- amyloid .
目的：探讨Tau蛋白过度磷酸化对β淀粉样蛋白蛋白多肽生成是否存在影响。观察高胆固醇血症对淀粉样蛋白生成的影响。
方法：1．用蛋白磷酸酯酶抑制剂冈田酸(OA)在大鼠侧脑室内注射，连续三月。制作Tau蛋白过度磷酸化模型。用Morris水迷宫，免疫组织化学方法观察模型组大鼠行为学改变，及神经原纤维的缠结，淀粉样蛋
Background:
Alzheimer's disease (AD) is a neurodegenerative disorder that is characterized by neuronal loss and the formation of neuritic plaques, neurofibrillary tangles (NFTs), and neuropil threads.In recent 10years,lots of scholars support the hypothesis of amyloidrthe overexpression of Ap can lead to neurofibrillary tangles, further can lead to neuronal apoptosis and synapse disfunction.But we can not deplete the possible that the hyperphosphorylated tau protein can increase the expression of Ap.So the relation of hyperphosphorylated tau protein and Ap may not be simple;The cholesterol, or cholesterol metabolism, plays a role in the pathophysiology of AD. Cholesterol levels can modulate the enzymatic processing of the amyloid precursor protein (APP) and Ap production. Neurotoxic of amyloid can lead to neuronal apoptosis and show dementia in clinical.
Objective:
To explore the effect of hyperphosphorylated tau protein and hypercholesteremia on the expression of β- amyloid .
引文
1 Dennis J. Selkoe. Alzheimei's disease is a synaptic failure[J].Science 2002 vol 298.25.789-791.
2 Ling Y,Morgan K,Kalsheker N. Amyloid precursor protein(APP) and the biology of proteolytic processing:relevance to Alzheimei's disease[J].Int J Biochem Cell Biol, 2003, 35: 1505-1535.
3 Rochi A, Pellegrini S, Siciliano G, et al. Causative and susceptibility genes for Alzheimer's disease:a review[J]. Brain Res Buli. 2003.61:1-24.
4 Selkoe DJ, Schenk D. Alzheimer's disease: molecular understanding predicts amyloid-based the rapentics[J]. Annu Rev Pharmacol Toxicol, 2003, 43:545-584.
5 Coughlan CM, Breen KC .Factors influencing the processing and function of the amylid beta precursor protein-a potential therapeutic target in Alzheimer's disease? [J] Pharmacol Ther, 2000, 86(2):111-144.
6 Suh YH, cheler F, Amyloid precursor protein, presenilins, and alpha-synuelein:molecular pathogenesis and pharmacological applications in Azheimer's disease[J]. Pharmacol Rev. 2002, 54(3):469-525.
7 Zohar O.et al. Quantification and distribution of-secretase alternative splice variants in the rat and human brain [J]. Molecular Brain research. 2003.115(1):63-68.
8 Annaert W,Strooper BD, Acell biological perspective on Alzheimer's disease [J]. Annu Rev Cell Dev Biol, 2002, 18:25-51.
9 Suh YH, cheler F, Amyloid precursor protein, presenilins, and alpha-synuelein:molecular pathogenesis and pharmacological applications in Azheimer's disease[J]. PharmacolRev. 2002, 54(3):469-525.
10 Strooper BD, Aph-1, Pen-2, and Nicastrin with presenilin generate an active γ-cecretase complex[J]. Neuron, 2003, 38: 9-12.
11 Farris W, Mansourian S, Chang Y, etal. Insulin degradin enzyme regulates the levels of insulin, amyloidbeta protein and the beta amyloid precursor rprotein intracellular domain in vivo[J]. Proc Natl Acad Sci USA, 2003, 100(7):4162-4167.
12 Ling X, Martins RN, Racchi M, et al. Amyloid beta antagonizes insulin promoted secretion of the amyloid beta protein precursor[J]. J Alzheimers Dis, 2002, 4(5):369-374.
13 Selkoe DJ. Alzheimer's disease is a synaptic failure[J]. Science, 2002, 298(5594):789-791.
14 Lambert MP, Viola KL, Chromy BA, et al. Vaccination with soluble Abeta oligomers generates toxicity-neutralizing antibodies[J]. J Neurochem, 2001, 79(3):595-605.
15 Yankner BA. Mechanisms of neuronal degeneration in Alzheimer's disease[J]. Neuron, 1996, 16(5):921-932.
16 Strausak D, Mercer JFB, Dieter HH, et al. Copper in disorder with neurological symptoms: Alzheimer's, Menkes, and Wilson diseases[J]. Brain Res Bul, 2001, 55(2):175-185.
17 Sies H. Biochemistry of Oxidative Stress[M]. Angew Che Int Ed Engl, 1986. 1058-1079.
18 Schubert D, Piasecki D. Oxidative glutamate toxicity can be a component of the excitotoxicity cascade[J]. J Neurosci, 2001, 21:7455-7462.
19 Zhang Y, Cynthia G, Andren LB. Selective and protracted apoptosis in human primary neurons microinjection with active caspase 3, 6, 7and 8[J]. J Neurosci, 2000, 20(22):8384-8389.
20 Nishimura I, Uetsuki T, Kuwako K, et al. Cell death induced by a caspase cleaved transmembrane fragment of the Alzheimeramyloid precursor protein[J]. Cell Death Differ, 2002, 9(2) 199-208.
21 Rohn TT, Head E, Nesse WH, et al. Activation of caspase 8 in the Alzheimer's disease brain[J]. Neurobiol Dis, 2001, 8 (6): 1006-1016.
22 Chung CW, Song YH, Kim IK, et al. Proapoptotic effects of tau cleavage product generated by caspase 3[J]. Neurobiol Dis, 2001, 8(1):162-172.
23 Morishima YS, Gotoh Y, Zieg J, et al. β-Amyloid induce neuronal apoptosis via a mechanism that involves the c-JunN-terminal Kinase pathway and the induction of Fas ligand[J] Brain Res, 2002, 931(2):117-125.
24 Wyss Coray T, Yan F, Lin AH, et al. Prominent neuro degeneration and increased plaque formation in complement-inhibited Alzheimer's mice[J]. Proc Natl Acad Sci USA, 2002, 99 (16): 10837-10842.
25 Lue LF, Walker DG. Modeling Alzheimer's disease immune therapy mechanisms:interactions of human post mortem microglia with antibody-opsonized amyloid beta peptid[J]. J Neurosci Res, 2002, 70(4):599-610.
26 Matsuoka Y, Picciano M, Malester B, et al. Inflammatory responses to amyloidosis in a transgenic mouse model of Alzheimer's disease[J]. Am J Pathol, 2001, 158(4):1345-1354.
27 Xiang Z, Ho L, Yemul S, et al. Cyclooxygenase-2 promote amyloid plaque deposition in a mouse model of Alzheimer's disease neuropathology[J]. GeneExpr, 2002, 10(5-6):271-278.
28 Avramovich Y, Amit T, Youdim MB, et al. Non-steroidal anti-inflammatory drugs stimulate secretion of non-amyloido-genic precursor protein[J]. JBiolChem, 2002, 277(35) 31466-31473.
29 Lewis J, Dickson DW, Lin WL, et al. Enhanced neurofibrillar degeneration in transgenic mice expressing mutant tau and APP[J] Science, 2001, 293(5534):1487-1491.
30 Kozikowski AP, Nowak I, Petukhov PA, et al. New a midebearing benzolactam-based protein kinase C modulators induce enhanced secretion of the amyloid precursor rprotein metabolit sAPP alpha[J]. J Med Chem, 2003, 46(3):364-373.
31 Mudger A, Chapman S, Richardson J, et al. Dishevelled regulates the metabolism of amyloid precursor protein via protein kinase c/Mitogen-Activated protein kinase and c-Jun terminal kinase[J]. J Neurosci, 2001, 21(14):4987-4995.
32 Trojanowski JQ, Lee VM. The role of tau in Alzheimer's disease. Med Clin North Am, 2002, 86:615-627.
33 ThomasF, JochenE, RolandB. Tau mediated cytotoxicity in a pseudo hyperphosphorylation model of Alzheimer's disease [J]. JNeuro science, 2002, 22(22):9733-41.
34 Gong CX, Wegiel J, Lidsky T, et al. Regulation of phosphorylation of neuronal microtubule associated proteins MAP1b and MAP2 by protein pho sphatase 2A and 2B in rat brain[J]. Brain Res, 2000, 853:299-309.
35 Alonso AD, Grundke Iqbal I, Barra HS, et al. Abnormal phosphorylation of tau and the mechanism of Alzheimer neurofibrllary degeneration:sequestration of microtubule associated proteinsl and 2 the disassembly of microtubules by the abnormal tau[J]. Proc NATL Acad Sci USA, 1997, 94:298-303.
36 MosrschR, SimonW, ColemanPD. Neurons may live for decades with neurofibrillary tangles[J]. Neuropathol and ExpNeurol, 1999, 58:188-97.
37 Goedert M, Hasegawa M, Jakes R etal. Phosphorylation of microtubule associated protein tau by stress activated protein kinases [J]FEBSLett, 1997, 409:57-62.
38 Drewes G, Ebneth A, Preuss U etal. MARK, a novel family of protein kinases that phosphorylate microtubule associated proteinsand trigger micro tubule disruption [J]. Cell, 1997, 89: 297-308.
39 Kim DH, Hong HN, Lee JH, et al. Okadaic acid induced cycloheximide and caspase sensitive apoptosis in immature neurons [J]. Mol Cell, 2000, 10(1): 83-89.
40 [Kim DH, Su J, Cotman CW. Sequence of neuro degeneration and accumulation of phosphorylated tau in cultured neuronsafer okadaic acid treatment [J]. Brain Res, 1999, 839: 253-262.
41 Wang JZ, Grundke Iqbal I, Iqbal K, et al. Restoration of biological activity of Alzheimer abnormally phosphorylated tau by dephosphorylation with protein phosphatase 1, 2A and 2B [J]. Mol Brain Res, 1996, 38: 200-208.
42 Tanaka T, Zhong J, Iqbal K, et al. The regulation of phosphorylation of τ in SY5Y neuroblastoma cells: the role of protein phosphatases [J]. FEBS Letters, 1998, 426: 248-254.
43 Giasson BI, Cromlish JA. et al. Activation of cyclic AMP-dependent protein kinase in okadaic acid treated neurons potentiates neurofilament fragmentation and stimulates phosphorylation of ser2 in the low-molecular-mass neurofilamentsubunit [J]. J Neurochem. 1996. 66(3): 1207-1213.
44 Islam K, Levy E. Carboxyl-terminal fragments of beta amyloid precursor protein bind to microtubules and the associated protein tau [J]. Am JPathol, 1997, 151: 265-71.
45 Schmidt ML, Di Dario AG, Lee VM, Trojanowski JQ. An extensive Net work of PHF tau-rich dystrophic neuritis permeates neocortex and nearly all neuritic and diffuse amyloid plaques in Alzheime rdiseas [J]. FEBS Lett, 1994, 344: 69-73.
46 吴琪，方莹莹，郑树森，钱采韵．海马内注射纤丝状Aβ42诱导tau异常磷酸化的研究[J]．中国神经精神疾病杂志，2003，2(3)：175-6．
47 Busciglio J, Lorenzo A, Yeh J et al. β Amyloid fibrils induce tau phosphorylation and loss of microtubule binding [J]. Neuron, 1995, 1(4): 879.48 洪道俊，裴爱琳，陆世铎等．调心方对大鼠杏仁核注射Aβ25～35致P35和tau蛋白磷酸化的调节作用[J]．中华老年医学杂志，2003，22(11)：673-6．
49 Khatoon S, Grundke-Iqbal I, Iqbal K. Brain levels of microtubule as associated protein tau are elevated in Alzheimer's disease: a radioimmuno slot-blot assay for nanograms of the protein [J]. J Neurochem 1992, 59(2): 750-3.
50 Stamer K, Vogel R, Thies E et al. Tau blocks traffic of organelles, neurofilaments, and APP vesicles in neurons and enhances oxidative stress [J]. J CellBiol, 2002, 156(6): 1051-63.
51 Xu H, Sweeney D, Wang R et al. Generation of Alzheimer Beta amyloid protein in the trans-Golgi network in the apparent absence of vesicle formation [J]. Proc Natl Acad Sci USA, 1997, 94: 3748-52.
52 Rapoport M, Dawson HN, Binder LI et al. Tau is essential to beta amyloid-induced neurotoxicity [J]. Proc Natl Acad Sci USA, 2002, 99(9): 6364-9.
53 Perez M, Hernandez F, Gomez Ramos A et al. Formation of aberrant phosphotau fibrilla rpolymers In neural cultured cells [J]. Eur J Biochem, 2002, 269: 1484-9.
54 Sayre LM, Zelasko DA, harris PL et al. 4-Hydroxynonenal-derived advanced lipid peroxidation end products are Increased In Alzheim disease [J]. J Neruochem, 1997, 68: 2092-7.
55 Pratico D, Uryu K, Leight S et al. Increased lipid peroxidation precedes amyloid plaque formation In an animal model of Alzheimer amyloidosis [J]. JNeruosci, 2001, 21: 4183-4187.
56 Kim DH, Su J, Cotman CW. Sequence of neuro degeneration and accumulation of phosphorylated tau in cultured neuronsafer okadaic acid treatment [J]. Brain Res, 1999, 839: 253-262.
57 Elkins JS, O'Meara ES, Longstreth WT Jr, et al. Stroke risk factors and loss of high cognitive function [J]. Neurology,??2004, 63:793-799.
58 Casserly I, Topol E. Convergence of atherosclerosis and Alzheimer's disease:inflammation, cholesterol, and misfolded proteins[J]. Lancet, 2004, 363:1139-1146.
59 de la Torre JC. Alzheimer's disease as a vascular disorder:nosological evidence[J]. Stroke, 2002, 33:1152-1162.
60 Whitmer RA, Sidney S, Selby J, et al. Midlife cardiovascular risk factors and risk of dementia in late life[J]. Neurology. 2005. 64:277-281.
61 Reitz C, Tang MX, Luchsinger J, et al. Relation of plasma lipids to Alzheimer disease and vascular dementia[J]. Arch Neurol, 2004, 61:705-714.
62 Dufoui 1C, Richard F, Fievet N, et al. APOE genotype, cholestero level, lipid lowering treatment, and dementia:the Three City Study[J]. Neurology, 2005, 64:1531-1538.
63 Rodriguez EG, Dodge HH, Birzescu MA, et al. Use of lipid lowering drugs in older adults with and without dementia:a community-based epidemiological study[J]. J Am Geriatr Soc, 2002, 50:1852-1856.
64 Evans RM, Hui S, Perkins A, et al. Cholesterol and APOE genotype interact to influence Alzheimer disease progression[J]. Neurology, 2004, 62:1869-1871.
65 Mielke MM, Zandi PP, Sj?gren M, et al. High total cholesterol levels in late life associated with a reduced risk of dementia[J]. Neurology, 2005. 64:1689-1695.
66 Notkola IL, Sulkava R, pekkanen J, et al. Serum total cholesterol, apolipoprotein E epsilon 4 allele, and Alzheimer's disease[J]. Neuroepidemiology, 1998. 17:14-20.
67 Bjorkhem I, Meaney S. Brain cholesterol:long secret life behind a barrier[J]. Arterioscler Thromb Vasc Biol, 2004, 24:806-815.
68 Locatelli S, Lutjohann D, Schmidt HH. Reduction of plasma24S-hydroxylcholesterol(cerebrosterol) levels using high dosage simvastatin in patients with hypercholesterolemia:evidence that simvastatin affects cholesterol metabolism in the human brain[J]. Arch Neurol, 2002, 59:213-216.
69 Vega GL, Weiner MF, Lipton AM, et al. Reduction in levels of 24S-hydroxycholesterol by statin treatment in patients with Alzheimer's disease[J]. Arch Neurology, 2003, 60:510-515.
70 Jick H, Zornberg GL, Jick SS, et al. Statins and the risk of dementia[J]. Lancet, 2000, 356:1627-1631.
71 Wolozin B, Kelllman W, Ruosseau P, et al. Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors[J]. Arch Neurol, 2000, 57: 1439-1443.
72 Rockwood K, Kirkland S, Hongan DB, et al. Use of lipid lowering agents, indication bias, and the risk of dementia in community dwelling elderly people[J]. Arch Neurol, 2002, 59:223-227.
73 Hajjar I, Schumpert J, Hirth V. The impact of the use of cognitive impairment[J]. J Gerontol A Biol Sci Med Sci. 2002, 57:M414-418.
74 Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20, 536 high risk individuals:a randomized placebo-controlled trial[J]. Lancet, 2002, 360:7-22.
75 Sparks DL, Sabbagh MN, Connor DJ, et al. Atorvastatin for the treatment of mild to moderate Alzheimer disease:preliminary results[J]. Arch Neurol. 2005, 62:753-757.
76 Wangstaff LR, Melinda WM, Arvik BM, et al. Statin associated memory loss:analysis of 60 case reports and review of the literature[J]. Pharmacotherapy. 2003, 23:871-880.
77 Naidu A, Xu Q, Catalano R et al. Secretion of apolipoprotein E by brain glia requires protein prenylation and is suppressedby statins [J]. Brain Res, 2002, 958: 100-111.
78 Gibson, Wood W, Eckert GP, Igbavboa U, et al. Amyloid β protein interactions with membranes and cholesterol: causes or causualties of Alzheimer's disease [J]. Biochim Biophys Acta. 2003. 1610: 281-290.
79 Fassbender K, Sinons M, Bergmann C, et al. Simvastatin strongly reduces levels of Alzheimer's disease β amyloid peptides A β 42 and A β 40 in vitro and in vivo [J]. Proc Nat Acad Sci USA, 2001. 98: 5856-5861.
80 Law MR, Wald NJ, Rudnicka AR, et al. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis [J]. BMJ, 2003, 326: 1423.
81 Blauw GJ, Laggay AM, Smelt AH, et al. Stroke, statins and cholesterol. Ameta analysis of frandomized, placebo-controlled, double-blind trails with HMG-CoA reductase inhibitors [J]. Stroke, 1997, 28: 946-950.
82 Ridker PM, Rifain N, Pfeffer MA, et al. Long term effect of pravastati on plasma concentration of C reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators [J]. Circulation, 1999, 100: 230-235.
83 Das UN. Stains and the prevention of dementia [J]. CAMJ. 2001. 165: 908-909.
84 Frank M. LaFerla Calcium dyshomeostasis and intracellular signaling in Alzheimer's disease [J]. Nature Reviews Neuroscience 2002. November Vol3: 862-872.
85 Sternbterger LA, Sternbterger NH, Aberrant neurofilament phosphorylation in Alzheimer's disease [J]. Proc Natl Acad Sci USA, 1985, 4274-4276.
86 李先涛 王群 魏泽兰等。Alzheimer样磷酸酯酶缺陷导致神经细丝异常磷酸化和聚积[J]，中国医学科学院学报，2001．??10：439-444．
87 Lusis AJ. Atherosclerosis [J]. Nature. 2000; 407: 233-241.
88 Ross R. Atherosclerosis: An inflammatory disease [J]. N Engl J Med. 1999; 340: 115-126.
89 Goodenough DA, Goliger JA, Paul DL. Connexins, connexons, and intercellular communication [J]. Annu Rev Biochem. 1996; 65: 475-502.
90 Willecke K, Eiberger J, Degen J, et al. Structural and functional diversity of connexin genes in the mouse and human genome [J]. Biol Chem. 2002; 383: 725-737.
91 Kumar N, Gilula NB. The gap junction communication channel [J]. Cell. 1996; 84: 381-388.
92 药立波．医学分子生物学实验技术[M]．北京：人民卫生出版社 2002．44-52．
93 Takemoto M, Liao JK. Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzymeA reductase inhibitors [J]. Arterioscler Thromb Vasc Biol. 2001; 21: 1712-1719.
94 Gabriels JE, Paul DL. Connexin43 is highly localized to sites of disturbed flow in rat aortic endothelium but connexin37 and connexin40 are more uniformly distributed [J]. Circ Res. 1998; 83: 636-643.
95 Kwak BR, Mulhaupt F, Veillard N, et al. Altered pattern of vascular connexin expression in atherosclerotic plaques [J]. Arterioscler Thromb Vasc Biol. 2002; 22: 225-230.
96 Libby P. Current concepts of the pathogenesis of the acute coronary syndromes [J]. Circulation. 2001; 104: 365-372.
97 Kita T, Brown MS, Goldstein JL. Feedback regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase in livers of mice treated with mevinolin, a competitive inhibitor of the reductase [J]. J Clin Invest. 1980; 66: 1094-1100.
98 Kwak BR, Jongsma HJ. Selective inhibition of gap junction??channel activity by synthetic peptides[J]. J Physiol. 1999; 516: 679-685.
99 Frears, E. R, Stephens, D. J, Walters, C. E, Davies, H, & Austen, B. M. [J]. The role of cholesterol in the biosynthesis of betaamyloid. NeuroReport, 1999, 10:1699-1705.
100 Liu, H. C, Hong, C. J, Wang, S. J, Fuh, J. L, Wang, P. N, Shyu, H. Y, & Teng, E. L. ApoE genotype in relation to AD and cholesterol: A study of 2, 326 Chinese adults[J]. Neurology, 1999, 53:962-966.
101 Frears, E. R, Stephens, D. J, Walters, C. E, Davies, H, & Austen, B. M. The role of cholesterol in the biosynthesis of beta-amyloid [J]. NeuroReport, 1999, 10:1699-1705.
102 Papolla MA. Bryant-Thomas TK, Herbert D. Mild hypercholesterolemia is an early risk factor for the development off Alzheimer amyloid pathology[J]. Neurology, 2003. 199.
103 Schroeder, F, Woodford, J. K, Kavecansky, J, Wood, W. G, &Joiner, C. Cholesterol domains in biological membranes[J]. Mol. Membr. Biol, 1995, 12:113-119.
104 Ikezu, T, Trapp, B. D, Song, K. S, Schlegel, A, Lisanti, M. P, & Okamoto, T. Caveolae, plasma membrane microdomains for alpha-secretase-mediated processing of the amyloid precursor protein[J]. J. Biol. Chem, 1998, 273:10485-10495.
2 Ling Y,Morgan K,Kalsheker N. Amyloid precursor protein(APP) and the biology of proteolytic processing:relevance to Alzheimei's disease[J].Int J Biochem Cell Biol, 2003, 35: 1505-1535.
3 Rochi A, Pellegrini S, Siciliano G, et al. Causative and susceptibility genes for Alzheimer's disease:a review[J]. Brain Res Buli. 2003.61:1-24.
4 Selkoe DJ, Schenk D. Alzheimer's disease: molecular understanding predicts amyloid-based the rapentics[J]. Annu Rev Pharmacol Toxicol, 2003, 43:545-584.
5 Coughlan CM, Breen KC .Factors influencing the processing and function of the amylid beta precursor protein-a potential therapeutic target in Alzheimer's disease? [J] Pharmacol Ther, 2000, 86(2):111-144.
6 Suh YH, cheler F, Amyloid precursor protein, presenilins, and alpha-synuelein:molecular pathogenesis and pharmacological applications in Azheimer's disease[J]. Pharmacol Rev. 2002, 54(3):469-525.
7 Zohar O.et al. Quantification and distribution of-secretase alternative splice variants in the rat and human brain [J]. Molecular Brain research. 2003.115(1):63-68.
8 Annaert W,Strooper BD, Acell biological perspective on Alzheimer's disease [J]. Annu Rev Cell Dev Biol, 2002, 18:25-51.
9 Suh YH, cheler F, Amyloid precursor protein, presenilins, and alpha-synuelein:molecular pathogenesis and pharmacological applications in Azheimer's disease[J]. PharmacolRev. 2002, 54(3):469-525.
10 Strooper BD, Aph-1, Pen-2, and Nicastrin with presenilin generate an active γ-cecretase complex[J]. Neuron, 2003, 38: 9-12.
11 Farris W, Mansourian S, Chang Y, etal. Insulin degradin enzyme regulates the levels of insulin, amyloidbeta protein and the beta amyloid precursor rprotein intracellular domain in vivo[J]. Proc Natl Acad Sci USA, 2003, 100(7):4162-4167.
12 Ling X, Martins RN, Racchi M, et al. Amyloid beta antagonizes insulin promoted secretion of the amyloid beta protein precursor[J]. J Alzheimers Dis, 2002, 4(5):369-374.
13 Selkoe DJ. Alzheimer's disease is a synaptic failure[J]. Science, 2002, 298(5594):789-791.
14 Lambert MP, Viola KL, Chromy BA, et al. Vaccination with soluble Abeta oligomers generates toxicity-neutralizing antibodies[J]. J Neurochem, 2001, 79(3):595-605.
15 Yankner BA. Mechanisms of neuronal degeneration in Alzheimer's disease[J]. Neuron, 1996, 16(5):921-932.
16 Strausak D, Mercer JFB, Dieter HH, et al. Copper in disorder with neurological symptoms: Alzheimer's, Menkes, and Wilson diseases[J]. Brain Res Bul, 2001, 55(2):175-185.
17 Sies H. Biochemistry of Oxidative Stress[M]. Angew Che Int Ed Engl, 1986. 1058-1079.
18 Schubert D, Piasecki D. Oxidative glutamate toxicity can be a component of the excitotoxicity cascade[J]. J Neurosci, 2001, 21:7455-7462.
19 Zhang Y, Cynthia G, Andren LB. Selective and protracted apoptosis in human primary neurons microinjection with active caspase 3, 6, 7and 8[J]. J Neurosci, 2000, 20(22):8384-8389.
20 Nishimura I, Uetsuki T, Kuwako K, et al. Cell death induced by a caspase cleaved transmembrane fragment of the Alzheimeramyloid precursor protein[J]. Cell Death Differ, 2002, 9(2) 199-208.
21 Rohn TT, Head E, Nesse WH, et al. Activation of caspase 8 in the Alzheimer's disease brain[J]. Neurobiol Dis, 2001, 8 (6): 1006-1016.
22 Chung CW, Song YH, Kim IK, et al. Proapoptotic effects of tau cleavage product generated by caspase 3[J]. Neurobiol Dis, 2001, 8(1):162-172.
23 Morishima YS, Gotoh Y, Zieg J, et al. β-Amyloid induce neuronal apoptosis via a mechanism that involves the c-JunN-terminal Kinase pathway and the induction of Fas ligand[J] Brain Res, 2002, 931(2):117-125.
24 Wyss Coray T, Yan F, Lin AH, et al. Prominent neuro degeneration and increased plaque formation in complement-inhibited Alzheimer's mice[J]. Proc Natl Acad Sci USA, 2002, 99 (16): 10837-10842.
25 Lue LF, Walker DG. Modeling Alzheimer's disease immune therapy mechanisms:interactions of human post mortem microglia with antibody-opsonized amyloid beta peptid[J]. J Neurosci Res, 2002, 70(4):599-610.
26 Matsuoka Y, Picciano M, Malester B, et al. Inflammatory responses to amyloidosis in a transgenic mouse model of Alzheimer's disease[J]. Am J Pathol, 2001, 158(4):1345-1354.
27 Xiang Z, Ho L, Yemul S, et al. Cyclooxygenase-2 promote amyloid plaque deposition in a mouse model of Alzheimer's disease neuropathology[J]. GeneExpr, 2002, 10(5-6):271-278.
28 Avramovich Y, Amit T, Youdim MB, et al. Non-steroidal anti-inflammatory drugs stimulate secretion of non-amyloido-genic precursor protein[J]. JBiolChem, 2002, 277(35) 31466-31473.
29 Lewis J, Dickson DW, Lin WL, et al. Enhanced neurofibrillar degeneration in transgenic mice expressing mutant tau and APP[J] Science, 2001, 293(5534):1487-1491.
30 Kozikowski AP, Nowak I, Petukhov PA, et al. New a midebearing benzolactam-based protein kinase C modulators induce enhanced secretion of the amyloid precursor rprotein metabolit sAPP alpha[J]. J Med Chem, 2003, 46(3):364-373.
31 Mudger A, Chapman S, Richardson J, et al. Dishevelled regulates the metabolism of amyloid precursor protein via protein kinase c/Mitogen-Activated protein kinase and c-Jun terminal kinase[J]. J Neurosci, 2001, 21(14):4987-4995.
32 Trojanowski JQ, Lee VM. The role of tau in Alzheimer's disease. Med Clin North Am, 2002, 86:615-627.
33 ThomasF, JochenE, RolandB. Tau mediated cytotoxicity in a pseudo hyperphosphorylation model of Alzheimer's disease [J]. JNeuro science, 2002, 22(22):9733-41.
34 Gong CX, Wegiel J, Lidsky T, et al. Regulation of phosphorylation of neuronal microtubule associated proteins MAP1b and MAP2 by protein pho sphatase 2A and 2B in rat brain[J]. Brain Res, 2000, 853:299-309.
35 Alonso AD, Grundke Iqbal I, Barra HS, et al. Abnormal phosphorylation of tau and the mechanism of Alzheimer neurofibrllary degeneration:sequestration of microtubule associated proteinsl and 2 the disassembly of microtubules by the abnormal tau[J]. Proc NATL Acad Sci USA, 1997, 94:298-303.
36 MosrschR, SimonW, ColemanPD. Neurons may live for decades with neurofibrillary tangles[J]. Neuropathol and ExpNeurol, 1999, 58:188-97.
37 Goedert M, Hasegawa M, Jakes R etal. Phosphorylation of microtubule associated protein tau by stress activated protein kinases [J]FEBSLett, 1997, 409:57-62.
38 Drewes G, Ebneth A, Preuss U etal. MARK, a novel family of protein kinases that phosphorylate microtubule associated proteinsand trigger micro tubule disruption [J]. Cell, 1997, 89: 297-308.
39 Kim DH, Hong HN, Lee JH, et al. Okadaic acid induced cycloheximide and caspase sensitive apoptosis in immature neurons [J]. Mol Cell, 2000, 10(1): 83-89.
40 [Kim DH, Su J, Cotman CW. Sequence of neuro degeneration and accumulation of phosphorylated tau in cultured neuronsafer okadaic acid treatment [J]. Brain Res, 1999, 839: 253-262.
41 Wang JZ, Grundke Iqbal I, Iqbal K, et al. Restoration of biological activity of Alzheimer abnormally phosphorylated tau by dephosphorylation with protein phosphatase 1, 2A and 2B [J]. Mol Brain Res, 1996, 38: 200-208.
42 Tanaka T, Zhong J, Iqbal K, et al. The regulation of phosphorylation of τ in SY5Y neuroblastoma cells: the role of protein phosphatases [J]. FEBS Letters, 1998, 426: 248-254.
43 Giasson BI, Cromlish JA. et al. Activation of cyclic AMP-dependent protein kinase in okadaic acid treated neurons potentiates neurofilament fragmentation and stimulates phosphorylation of ser2 in the low-molecular-mass neurofilamentsubunit [J]. J Neurochem. 1996. 66(3): 1207-1213.
44 Islam K, Levy E. Carboxyl-terminal fragments of beta amyloid precursor protein bind to microtubules and the associated protein tau [J]. Am JPathol, 1997, 151: 265-71.
45 Schmidt ML, Di Dario AG, Lee VM, Trojanowski JQ. An extensive Net work of PHF tau-rich dystrophic neuritis permeates neocortex and nearly all neuritic and diffuse amyloid plaques in Alzheime rdiseas [J]. FEBS Lett, 1994, 344: 69-73.
46 吴琪，方莹莹，郑树森，钱采韵．海马内注射纤丝状Aβ42诱导tau异常磷酸化的研究[J]．中国神经精神疾病杂志，2003，2(3)：175-6．
47 Busciglio J, Lorenzo A, Yeh J et al. β Amyloid fibrils induce tau phosphorylation and loss of microtubule binding [J]. Neuron, 1995, 1(4): 879.48 洪道俊，裴爱琳，陆世铎等．调心方对大鼠杏仁核注射Aβ25～35致P35和tau蛋白磷酸化的调节作用[J]．中华老年医学杂志，2003，22(11)：673-6．
49 Khatoon S, Grundke-Iqbal I, Iqbal K. Brain levels of microtubule as associated protein tau are elevated in Alzheimer's disease: a radioimmuno slot-blot assay for nanograms of the protein [J]. J Neurochem 1992, 59(2): 750-3.
50 Stamer K, Vogel R, Thies E et al. Tau blocks traffic of organelles, neurofilaments, and APP vesicles in neurons and enhances oxidative stress [J]. J CellBiol, 2002, 156(6): 1051-63.
51 Xu H, Sweeney D, Wang R et al. Generation of Alzheimer Beta amyloid protein in the trans-Golgi network in the apparent absence of vesicle formation [J]. Proc Natl Acad Sci USA, 1997, 94: 3748-52.
52 Rapoport M, Dawson HN, Binder LI et al. Tau is essential to beta amyloid-induced neurotoxicity [J]. Proc Natl Acad Sci USA, 2002, 99(9): 6364-9.
53 Perez M, Hernandez F, Gomez Ramos A et al. Formation of aberrant phosphotau fibrilla rpolymers In neural cultured cells [J]. Eur J Biochem, 2002, 269: 1484-9.
54 Sayre LM, Zelasko DA, harris PL et al. 4-Hydroxynonenal-derived advanced lipid peroxidation end products are Increased In Alzheim disease [J]. J Neruochem, 1997, 68: 2092-7.
55 Pratico D, Uryu K, Leight S et al. Increased lipid peroxidation precedes amyloid plaque formation In an animal model of Alzheimer amyloidosis [J]. JNeruosci, 2001, 21: 4183-4187.
56 Kim DH, Su J, Cotman CW. Sequence of neuro degeneration and accumulation of phosphorylated tau in cultured neuronsafer okadaic acid treatment [J]. Brain Res, 1999, 839: 253-262.
57 Elkins JS, O'Meara ES, Longstreth WT Jr, et al. Stroke risk factors and loss of high cognitive function [J]. Neurology,??2004, 63:793-799.
58 Casserly I, Topol E. Convergence of atherosclerosis and Alzheimer's disease:inflammation, cholesterol, and misfolded proteins[J]. Lancet, 2004, 363:1139-1146.
59 de la Torre JC. Alzheimer's disease as a vascular disorder:nosological evidence[J]. Stroke, 2002, 33:1152-1162.
60 Whitmer RA, Sidney S, Selby J, et al. Midlife cardiovascular risk factors and risk of dementia in late life[J]. Neurology. 2005. 64:277-281.
61 Reitz C, Tang MX, Luchsinger J, et al. Relation of plasma lipids to Alzheimer disease and vascular dementia[J]. Arch Neurol, 2004, 61:705-714.
62 Dufoui 1C, Richard F, Fievet N, et al. APOE genotype, cholestero level, lipid lowering treatment, and dementia:the Three City Study[J]. Neurology, 2005, 64:1531-1538.
63 Rodriguez EG, Dodge HH, Birzescu MA, et al. Use of lipid lowering drugs in older adults with and without dementia:a community-based epidemiological study[J]. J Am Geriatr Soc, 2002, 50:1852-1856.
64 Evans RM, Hui S, Perkins A, et al. Cholesterol and APOE genotype interact to influence Alzheimer disease progression[J]. Neurology, 2004, 62:1869-1871.
65 Mielke MM, Zandi PP, Sj?gren M, et al. High total cholesterol levels in late life associated with a reduced risk of dementia[J]. Neurology, 2005. 64:1689-1695.
66 Notkola IL, Sulkava R, pekkanen J, et al. Serum total cholesterol, apolipoprotein E epsilon 4 allele, and Alzheimer's disease[J]. Neuroepidemiology, 1998. 17:14-20.
67 Bjorkhem I, Meaney S. Brain cholesterol:long secret life behind a barrier[J]. Arterioscler Thromb Vasc Biol, 2004, 24:806-815.
68 Locatelli S, Lutjohann D, Schmidt HH. Reduction of plasma24S-hydroxylcholesterol(cerebrosterol) levels using high dosage simvastatin in patients with hypercholesterolemia:evidence that simvastatin affects cholesterol metabolism in the human brain[J]. Arch Neurol, 2002, 59:213-216.
69 Vega GL, Weiner MF, Lipton AM, et al. Reduction in levels of 24S-hydroxycholesterol by statin treatment in patients with Alzheimer's disease[J]. Arch Neurology, 2003, 60:510-515.
70 Jick H, Zornberg GL, Jick SS, et al. Statins and the risk of dementia[J]. Lancet, 2000, 356:1627-1631.
71 Wolozin B, Kelllman W, Ruosseau P, et al. Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors[J]. Arch Neurol, 2000, 57: 1439-1443.
72 Rockwood K, Kirkland S, Hongan DB, et al. Use of lipid lowering agents, indication bias, and the risk of dementia in community dwelling elderly people[J]. Arch Neurol, 2002, 59:223-227.
73 Hajjar I, Schumpert J, Hirth V. The impact of the use of cognitive impairment[J]. J Gerontol A Biol Sci Med Sci. 2002, 57:M414-418.
74 Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20, 536 high risk individuals:a randomized placebo-controlled trial[J]. Lancet, 2002, 360:7-22.
75 Sparks DL, Sabbagh MN, Connor DJ, et al. Atorvastatin for the treatment of mild to moderate Alzheimer disease:preliminary results[J]. Arch Neurol. 2005, 62:753-757.
76 Wangstaff LR, Melinda WM, Arvik BM, et al. Statin associated memory loss:analysis of 60 case reports and review of the literature[J]. Pharmacotherapy. 2003, 23:871-880.
77 Naidu A, Xu Q, Catalano R et al. Secretion of apolipoprotein E by brain glia requires protein prenylation and is suppressedby statins [J]. Brain Res, 2002, 958: 100-111.
78 Gibson, Wood W, Eckert GP, Igbavboa U, et al. Amyloid β protein interactions with membranes and cholesterol: causes or causualties of Alzheimer's disease [J]. Biochim Biophys Acta. 2003. 1610: 281-290.
79 Fassbender K, Sinons M, Bergmann C, et al. Simvastatin strongly reduces levels of Alzheimer's disease β amyloid peptides A β 42 and A β 40 in vitro and in vivo [J]. Proc Nat Acad Sci USA, 2001. 98: 5856-5861.
80 Law MR, Wald NJ, Rudnicka AR, et al. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis [J]. BMJ, 2003, 326: 1423.
81 Blauw GJ, Laggay AM, Smelt AH, et al. Stroke, statins and cholesterol. Ameta analysis of frandomized, placebo-controlled, double-blind trails with HMG-CoA reductase inhibitors [J]. Stroke, 1997, 28: 946-950.
82 Ridker PM, Rifain N, Pfeffer MA, et al. Long term effect of pravastati on plasma concentration of C reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators [J]. Circulation, 1999, 100: 230-235.
83 Das UN. Stains and the prevention of dementia [J]. CAMJ. 2001. 165: 908-909.
84 Frank M. LaFerla Calcium dyshomeostasis and intracellular signaling in Alzheimer's disease [J]. Nature Reviews Neuroscience 2002. November Vol3: 862-872.
85 Sternbterger LA, Sternbterger NH, Aberrant neurofilament phosphorylation in Alzheimer's disease [J]. Proc Natl Acad Sci USA, 1985, 4274-4276.
86 李先涛 王群 魏泽兰等。Alzheimer样磷酸酯酶缺陷导致神经细丝异常磷酸化和聚积[J]，中国医学科学院学报，2001．??10：439-444．
87 Lusis AJ. Atherosclerosis [J]. Nature. 2000; 407: 233-241.
88 Ross R. Atherosclerosis: An inflammatory disease [J]. N Engl J Med. 1999; 340: 115-126.
89 Goodenough DA, Goliger JA, Paul DL. Connexins, connexons, and intercellular communication [J]. Annu Rev Biochem. 1996; 65: 475-502.
90 Willecke K, Eiberger J, Degen J, et al. Structural and functional diversity of connexin genes in the mouse and human genome [J]. Biol Chem. 2002; 383: 725-737.
91 Kumar N, Gilula NB. The gap junction communication channel [J]. Cell. 1996; 84: 381-388.
92 药立波．医学分子生物学实验技术[M]．北京：人民卫生出版社 2002．44-52．
93 Takemoto M, Liao JK. Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzymeA reductase inhibitors [J]. Arterioscler Thromb Vasc Biol. 2001; 21: 1712-1719.
94 Gabriels JE, Paul DL. Connexin43 is highly localized to sites of disturbed flow in rat aortic endothelium but connexin37 and connexin40 are more uniformly distributed [J]. Circ Res. 1998; 83: 636-643.
95 Kwak BR, Mulhaupt F, Veillard N, et al. Altered pattern of vascular connexin expression in atherosclerotic plaques [J]. Arterioscler Thromb Vasc Biol. 2002; 22: 225-230.
96 Libby P. Current concepts of the pathogenesis of the acute coronary syndromes [J]. Circulation. 2001; 104: 365-372.
97 Kita T, Brown MS, Goldstein JL. Feedback regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase in livers of mice treated with mevinolin, a competitive inhibitor of the reductase [J]. J Clin Invest. 1980; 66: 1094-1100.
98 Kwak BR, Jongsma HJ. Selective inhibition of gap junction??channel activity by synthetic peptides[J]. J Physiol. 1999; 516: 679-685.
99 Frears, E. R, Stephens, D. J, Walters, C. E, Davies, H, & Austen, B. M. [J]. The role of cholesterol in the biosynthesis of betaamyloid. NeuroReport, 1999, 10:1699-1705.
100 Liu, H. C, Hong, C. J, Wang, S. J, Fuh, J. L, Wang, P. N, Shyu, H. Y, & Teng, E. L. ApoE genotype in relation to AD and cholesterol: A study of 2, 326 Chinese adults[J]. Neurology, 1999, 53:962-966.
101 Frears, E. R, Stephens, D. J, Walters, C. E, Davies, H, & Austen, B. M. The role of cholesterol in the biosynthesis of beta-amyloid [J]. NeuroReport, 1999, 10:1699-1705.
102 Papolla MA. Bryant-Thomas TK, Herbert D. Mild hypercholesterolemia is an early risk factor for the development off Alzheimer amyloid pathology[J]. Neurology, 2003. 199.
103 Schroeder, F, Woodford, J. K, Kavecansky, J, Wood, W. G, &Joiner, C. Cholesterol domains in biological membranes[J]. Mol. Membr. Biol, 1995, 12:113-119.
104 Ikezu, T, Trapp, B. D, Song, K. S, Schlegel, A, Lisanti, M. P, & Okamoto, T. Caveolae, plasma membrane microdomains for alpha-secretase-mediated processing of the amyloid precursor protein[J]. J. Biol. Chem, 1998, 273:10485-10495.