摘要
阿尔茨海默病(Alzheimer's disease, AD)是目前导致痴呆最常见的原因,其发病机制尚不清楚,并且缺乏有效的治疗方法。富含丙氨酸的豆蔻酰化蛋白激酶C的作用底物(myristoylated alanine-rich C-kinase substrate, MARCKS)是在大脑中表达丰富的联系神经元表面信号与树突棘可塑性的重要膜蛋白,与学习记忆功能密切相关。β-淀粉样蛋白(βamyloid, Aβ)在神经元外沉积形成的老年斑是AD的特征性病理表现,同时它又是导致其它病理表现和痴呆症状的原因,AD除了老年斑和神经纤维缠结,树突棘可塑性降低也是AD的重要病理表现之一。树突棘可塑性决定于细胞骨架肌动蛋白的运动,该过程受细胞膜表面4,5二磷酸磷脂酰肌醇(Phosphatidylinositol 4,5-bisphosphate, PIP2)的控制。PIP2可以激活多种肌动蛋白结合蛋白,导致细胞骨架肌动蛋白的运动,进而使树突棘可塑性发生变化。MARCKS通过其效应区(effector domain, ED)分别与PIP2和纤维状肌动蛋白(fibrous actin, F-actin)结合。MARCKS在蛋白激酶C(protein kinase C, PKC)磷酸化或Ca2+的作用下,离开细胞膜,并释放PIP2和f-actin,使肌动蛋白结合蛋白被PIP2激活,并导致f-actin依赖性树突棘可塑性变化。故本研究以MARCKS为切入点,探索具有神经元毒性作用的Aβ(1-40)作用下老龄大鼠海马MARCKS的表达变化,并进一步探讨MARCKS变化导致的树突棘可塑性变化以及中药复方苁蓉益智胶囊对这一变化的作用,探讨中药治疗AD的新途径。
目的：
1.建立侧脑室一次性注射Aβ(1-40)至痴呆老龄大鼠模型,并评价该模型作为老年痴呆动物模型的有效性。
2.研究Aβ(1-40)对痴呆老龄大鼠海马MARCKS表达的影响,进一步探索MARCKS介导的树突棘可塑性的变化以及复方苁蓉益智胶囊对Aβ致痴呆老龄大鼠海马MARCKS表达,及其介导的树突棘可塑性变化的作用机制。
3.根据本研究结果,深入探讨AD的中医发病机制。
方法：
1对18-20月龄的老龄大鼠一次性侧脑室注射聚集态Aβ(1-40)建立模型,通过Morris水迷宫检测模型大鼠学习记忆功能,通过免疫组化检测海马Aβ(1-40)含量,通过病理检测,观察其海马病理变化,评价其表面效度；根据乙酰胆碱酯酶抑制剂安理申改善该模型学习记忆功能的有效性评价其预测效度；根据其导致痴呆的机理评价其结构效度。
2将大鼠随机分为年轻组、老龄组、假手术组、模型组、安理申组以及中药组,模型组、安理申组以及中药组一次性侧脑室注射聚集态Aβ(1-40)建立老龄大鼠痴呆模型。中药和安理申组分别予口服复方苁蓉益智胶囊和安理申溶液14d。通过行为学、ELISA、RT-PCR和westernblotting等检测方法,观察模型大鼠学习记忆功能、Aβ(1-40)、MARCKS mRNA和树突棘可塑性标记蛋白drebrin含量的变化。
结果：
1该模型的表面效度成立：该模型可以模拟AD样记忆障碍、海马Ap含量增多以及神经元丢失等病理表现；预测效度成立：乙酰胆碱酯酶抑制剂可以改善该模型的学习记忆功能,减少模型大鼠海马Ap的含量,减少其海马神经元的变性和凋亡；结构效度成立：Ap(1-40)导致的病理变化符合淀粉样蛋白级联假说。
2行为学检测表明模型组的学习记忆功能明显低于年轻组,安理申组和中药组大鼠的学习记忆功能明显高于模型组；模型组海马MARCKS mRNA比年轻组、老龄组及假手术组均明显升高(P<0.01)；模型组海马drebrin含量较年轻组、老龄组及假手术组均明显降低(P<0.01)；中药组海马MARCKS mRNA比模型组明显降低(P<0.01),安理申组海马MARCKS mRNA没有明显变化；中药组和安理申组海马drebrin含量与模型组相比无明显差别。
结论：
1侧脑室注射Ap(1-40)致痴呆老龄大鼠模型是用于研究AD发病机制以及新疗法的有效工具,尤其适合与Aβ相关的病理机制以及针对Aβ神经毒性治疗方法的研究。
2侧脑室注射Ap(1-40)可以明显增加老龄大鼠海马MARCKS mRNA的表达,降低树突棘可塑性,并且导致老龄大鼠学习记忆障碍。根据MARCKS与树突棘可塑性之间的关系,推断MARCKS升高,导致与树突棘可塑性变化的游离态PIP2减少,很可能是Ap(1-40)致神经元可塑性降低的关键环节。基于“毒损脑络”理论研制的具有益肾补肝,解毒通络作用的复方苁蓉益智胶囊能够降低脑室注射Ap(1-40)致痴呆老龄大鼠海马MARCKS mRNA的表达,从而改善痴呆老龄大鼠学习记忆功能。其是否能够通过调节MARCKS的含量来增加树突棘可塑性,还需要进一步的证明。
3.根据“毒损脑络”理论,对AD中医病机的探讨,发现Ap由人体产生,并可以导致神经元丢失,具有败坏形体的特征,属于中医“内生毒邪”的范畴。进一步思考“络”的含义,发现随年龄的增长,富含脂质的神经元细胞膜最易受到氧化损伤,并且细胞膜是联系细胞表面信号和细胞内功能变化的途径,是人体气机的重要通路,属于“络”的范畴。所以“毒损脑络”是AD的重要病机。
Alzheimer's disease (AD) is the most common cause of dementia. Mechanisms of its pathogenesis are not clear. And there is no effective treatment for it. P-amyloid protein(Aβ).deposition around neuron is a core pathology, which can cause the symptom of dementia, as well as other pathologies. In addition to senile plaque and neurofibrillary tangle, decreasing dendritic spine plasticity is also one of the key pathologies of AD. Spine plasticity is decided by the dynamic of Actin cytoskeleton. This procession is mediated by the actin binding protein activation by Phosphatidylinositol 4,5-bisphosphate (PIP2). Myristoylated alanine-rich C-kinase substrate (MARCKS), is a rich and important membrane protien in brain, which connect neuron signal with dendritic spine plasticity. MARCKS can bind to PIP2 and f-actin separately with its effecter domain. When phorsphorlated by PKC or interacted with Ca2+, MARCKS can leave membrane, at the same time, PIP2 and f-actin can be released. F-actin binding proteins can be activated, which can induce the f-actin depended dendritic spine plasticity. So, This PhD project aims to clarify the mechanism of the MARCKS alteration and the dendritic spine plasticity alteration mediated by it in AD animal model, as well as the mechanism of Chinese medicine effects.
Objective:
1. Establish and assess the validity of dementia model induced by AP protein intracranial injection, which is used for the research of Alzheimer's disease.
2. Observe the alteration of MARCKS mRNA and drebrin, which is a marker protein of dendritic spine plasticity, in hippocampus of old dementia rats induced by P-amyloid(Aβ)(1-40). Observe the effect of Fu Fang Cong Rong Yi Zhi capsule on the alteration of MARCKS mRNA and drebrin level in hippocampus of the dementia animal model.
4. Implore AD pathology in Chinese medicine on the base of this research.
Methods:
1. Establish the dementia old rat model induced byβ-amyloid protein intracerebroventrical injection. Face validity was assessed by behavior test, pathological; predictive validity was assessed by the effect of cholinesterase inhibitor on learning and membrane function improvement; construct validity was assessed by mechanism of the mechanism of Aβinducing dementia.
2. Animals were assigned randomly to young group, old group, sham operation group, model group, donepezil group and Chinese medicine group. Model, west and Chinese medicine group received Aβ(1-40) intracerebroventrical injection to build dementia animal model, and then Chinese and west medicine group received Fu Fang Cong Rong Yi Zhi capsule and donepezil for 14 days, respectively. Observe changes of behavior, Aβ(1-40), MARCKS mRNA and drebrin by morris test, RT-PCR, ELISA test and westernblotting respectively.
Results:
1. Face validity was supported:the model could mimic the memory impairments of Alzheimer's disease, Predictive validity was supported:cholinesterase inhibitor could improve the learning and memory function of the model; Construct validity was supported:The pathological changes induced by Aβ(1-40) were correspondent with the amyloid hypothesis of AD.
2. Learning and memory function of model group was decreased, compared with young group. Learning and memory function of Chinese and donepezil group were better than model group. MARCKS mRNA of model group was increased significantly, compared with young group, old group and sham operation group (P<0.01). Drebrin level of model group is decreased significantly, compared with young group, old group and sham operation group(P<0.01). MARCKS mRNA of Chinese medicine was increased significantly (P<0.01), campared with model group. There is no difference between drebrin level of Chinese medicine group, donepezil group and that of model group.
Conclusion:
1. This model could be used as an effective protocol for us to understand the neurobiology of AD and new therapy for it.
2. Aβ(1-40) can increase the level of MARCKS m RNA, decrease the level of drebrin in old rat hippocampus, as well as decrease the learning and memory function of old rats. So MARKS may play a key role in the process of neuroplasticity reduction caused by Aβ(1-40). Fu Fang Cong Rong Yi Zhi capsule with the effect of benefiting kidney and liver, clearing toxin and improving blood vessel, which is based on the hypothesis "toxin damaging luo of brain" can reduce the level of MARCKS mRNA in hippocampus of old dementia rats caused by Aβ(1-40), through which it can improve the learning and memory function of the dementia old rats. Whether this medicine can increase the dendritic spine plasticity through this pathway, needs to be researched more deeply.
3. Implore the pathology of AD in Chinese medicine, it is discovered that Aβhad the character of damaging of brain and marrow internal toxin, so it belongs to internal toxin, internal toxin damaging brain and marrow is also the pathology of the disease. Membrane is the most easily damaged by oxidation. Membrane is the important pathway for Qi circulation, which can be belonged to the definition of "luo" in Chinese medicine. The Chinese medicine hypothesis of "toxin damaging brain vessel" is an important pathology of AD.
引文
1. Zi lka N, Novak M. The tangled story of Alois Alzheimer. Bratisl Lek Listy,2006, 107(9-10):343-345.
2. Selkoe DJ. Alzheimer's disease:genes, proteins, and therapy. Physiol Rev.2001; 81(2): 741-766.
3. McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology,1984,34(7):939-944.
4. Meng-jie Dong, Bin Peng, Xiang-tong Lin. The prevalence of dementia in the People's Republic of China:a systematic analysis of 1980-2004 studies. Age and Ageing,2007, 36(6):619-624.
5. Goate A, Chartier Harlin MC, Mullan M, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature,1991, 349(6311):704-706
6. Sherrington R, Rogaev El, Liang Y, et al.Cloning of a gene bearing missense mutations in early6onset familial Alzheimer's disease. Nature,1995,375(6534):754-760.
7. Rogaev El, Sherrington R, Rogaeva EA, et al.Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature,1995,376(6543):775-778.
8. Strittmatter WJ, Weisgraber KH, Huang DY, et al. Binding of human apolipoprotein E to synthetic amyloid beta peptide:isoform-specific effects and implications for late6onset Alzheimer disease. Proc Natl Acad Sci U S A,1993,90(17):8098-8102.
9. Breitner JC, Welsh KA. Genes and recent development in the epidermiology of Alzheimer disease and related dementia. Epidemiol Rev,1995,17(1):39-47.
10. Desai AK, Grossberg GT. Diagnosis and treatment of Alzheimer's disease. Neurology, 2005,64(12):34-39.
11. Corder EH, Saunders AM, Strittmatter WJ, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families.Science,1993, 261(5123):921-923.
12. Emilien G, Durlach C, Minaker KL, et al. Alzheimer disease:neuropsychology and pharmacology. Basel, Switzerland, Birkhauser Verlag,2004:20-25,
13. Desai AK, Grossberg GT. Diagnosis and treatment of Alzheimer's disease. Neurology, 2005,64(12):34-39,
14. Lyketsos CG, Lopezo, Jones B, et al. Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment:results from the cardiovascular health study. JAMA, 2002,288 (12):1475-1483.
15. Gauthier L, Gauthier S. Assessment of functiona changes in Alzheimer's disease. Neuroepidemiology,1990,9 (4):183-188.
16. Scott WK, Edwards KB, Davis DR, et al.Risk of institutionalization among community long-term care clients with dementia. Gerontologist,1997,37(1):46-51.
17. Henderson VW, Mack W, Williams BW. Spatial disorientation in Alzheimer's disease. Arch Neurol.1989; 46(4):391-394,
18. Albert MS. Cognitive and neurobiologic markers of early Alzheimer disease. Proc Natl Acad Sci USA,1996,93(24):13547-13551,
19. Knopman DS, Boeve BF, Petersen RC. Essentials of the proper diagnoses of mild cognitive impairment, dementia, and major subtypes of dementia. Mayo Clin Proc,2003,78 (10):1290-1308,
20. Salmon DP, Thomas RG, Pay MM, et al. Alzheimer's disease can be accurately diagnosed in very mildly impaired individuals. Neurology,2002,59 (7):1022-1028,
21. Mintzer JE. What are the challenges faced by psychiatrists in the management of Alzheimer's disease? CNS Spectr 2004;9(suppl 5):13-15,
22. O'Brien JT, Colloby SJ, Pakrasi S, et al. α4β2 nicotinic receptor status in Alzheimer's disease using 123I-5IA-85380 single-photon-emission computed tomography. J Neurol Neurosurg Psychiatry,2007,78 (4):356-362.
23. Sobow T, Flirski M, Liberski PP. Amyloid-beta and tau proteins as biochemical markers of Alzheimer's disease. Acta Neurobiol Exp (Wars),2004,64 (1):53-70.
24. American College of Medical Genetics/American Society of Human Genetics Working Group on ApoE and Alzheimer disease. Statement on use of apolipoprotein E testing for Alzheimer disease. JAMA,1995,274 (1):1627-1629.
25. Doody RS, Winblad B, Jelic V. Alzheimer's disease and related disorders annual. New York:Martin Dunitz,2004:137-144.
26. Nhi-Ha Trinh, JenniferHoblyn, Subhanjoy Mohanty, et al.Efficacy of Cholinesterase Inhibitors in the Treatment of Neuropsychiatric Symptoms and Functional Impairment in Alzheimer Disease. JAMA,2003,289(2):210-216.
27. Reisberg B, Doody R, Stoffler A, et al. Memantine in moderate6to6severe Alzheimer's disease.N Engl J Med,2003,348 (4):1333-1341.
28. Holmes C. Genotype and phenotype in Alzheimer's disease. Br J Psychiatry 2002; 180 (2):131-134.
29. Mark P. Mattson.Pathways towards and away from Alzheimer's disease. Nature,2004,430 (5):631-639.
30. Asai, M. et al. Putative function of ADAM9, ADAM10, and ADAM17 as APP alpha-secretase.Biochem. Biophys.Res.Commun,2003,301(1)231-235.
31. Hardy, J. Amyloid, the presenilins and Alzheimer's disease. Trends Neurosci, 1997,20(4):154-159.
32. Selkoe DJ. Alzheimer's disease:genes, proteins, and therapy. Physiol Rev,2001,81(2): 741-766.
33. Mahley RW. Apolipoprotein E:cholesterol transport protein with expanding role in cell biology. Science,1998,240(4852):622-630.
34. Nathan BP, Bellosta S, Sanan DA, et al. Differential effects of apolipoproteins E3 and E4 on neuronal growth in vitro. Science,1994,264(5):850-852.
35. Irizarry MC, Rebeck GW, Cheung B, Bales K, Paul SM, Holzman D, Hyman BT. Modulation of A beta deposition in APP transgenic mice by an apolipoprotein E null background. Ann N Y Acad Sci,2000,920:171-178.
36. K.R. Bales, J.C. Dodart, R.B. DeMattos,et al.Apolipoprotein E, Amyloid, and Alzheimer Disease. Mol Interv,2002,2(6):363-375.
37. Salvatore O, Antonella C, Ian F. S, et al. A Dynamic Relationship between Intracellular and Extracellular Pools of Aβ. American Journal of Pathology,2006,168 (1):184-194.
38. B. De Strooper.Aph-1, Pen-2, and Nicastrin with Presenilin Generate an Active y-Secretase Complex. Neuron,38(1):9-12.
39. Brion JP, Anderton BH, Authelet M, et al. Neurofibrillary tangles and tau phosphorylation. Biochem Soc Symp,2001,67 (8):81-88.
40. Guillozet AL, Weintraub S, Mash DC, et al. Neurofibrillary tangles, amyloid, and memory in aging and mild cognitive impairment. Arch Neurol,2003,60 (5):729-736.
41. Gomez-Isla T, Richard H, Howard W, et al. Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer's disease. Ann. Neurol,1997,41 (1):17-24.
42. DeKosky ST, Scheff SW. Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity. Ann Neurol,1990,27(5):457-464.
43. Terry RD, Masliah E, Salmon DP, et al. Physical basis of cognitive alterations in Alzheimer's disease:synapse loss is the major correlate of cognitive impairment. Ann Neurol,1991,30(4):572-580.
44. Reddy, P.H. Differential loss of synaptic proteins in Alzheimer's disease:implications for synaptic dysfunction. J. Alzheimers Dis,2005,7(1):103-117.
45. Bertoni-Freddari. Synaptic structural dynamics and aging. Gerontology,1996,1996, 42:170-180.
46. Gylys, K.H. Synaptic changes in Alzheimer's disease:increased amyloid-beta and gliosis in surviving terminals is accompanied by decreased PSD-95 fluorescence..Am. J. Pathol,2004, 165(1):1809-1817.
47. Almeida, C.G. Beta-amyloid accumulation in APP mutant neurons reduces PSD-95 and GluRl in synapses. Neurobiol. Dis,2005,20(2):187-198.
48. Khatchaturian ZS. Diagnosis of Alzheimer's disease. Arch. Neurol,1985, 42(2):1097-1105.
49. Vickers JC, Dickson TC, Adlard PA, et al. The cause of neuronal degeneration in Alzheimer's disease. Prog Neurobiol,2000,60(2):139-165.
50. Satyabrata Kar, Stephen P.M. Slowikowski, David Westaway, Interactions between P-amyloid and central cholinergic neurons:implications for Alzheimer's disease. Psychiatry Neurosci 2004;29(6):427-441.
51. DeKosky ST, Scheff SW, Styren SD. Structural correlates of cognition in dementia: quantification and assessment of synapse change. Neurodegeneration 1996;5 (4):417-421.
52. Lander CJ, Lee JM. Pharmacological drug treatment of Alzheimer disease:the cholinergic hypothesis revisited. J Neuropathol Exp Neurol 1998;57 (8):719-731.
53. Nitsch RM, Slack BE, Wurtman RJ, et al. Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic cholinergic receptor. Science 1992;258 (5080):304-307.
54. Roberson MR, Harrell LE. Cholinergic and amyloid precursor protein metabolism. Brain Res Rev,1997,25 (1):50-69.
55. Kim SH, Kim YK, Jeong SJ, et al. Enhanced release of secreted form of Alzheimer's amyloid precursor protein from PC 12 cells by nicotine. Mol Pharmacol,1997,52 (3):430-436.
56. Mills J, Reiner PB. Regulation of amyloid precursor protein cleavage. J Neurochem, 1999,72(2):443-460.
57. Lin L, Georgievska B, Mattsson A, Isacson O. Cognitive changes and modified processing of amyloid precursor protein in the cortical and hippocampal system after cholinergic synapse loss and muscarinic receptor activation. Proc Natl Acad Sci U S A,1999, 96(4):12108-12113.
58. Hellstrom-Lindahl E. Modulation of P-amyloid precursor protein processing and tau phosphorylation by acetylcholine receptors. Eur J Pharmacol,2000,393(1):255-263.
59. Huang HM, Ou HC, Hsieh SJ. Amyloid beta peptide impaired carbachol but not glutamate-mediated phosphoinositide pathways in cultured rat cortical neurons.Neurochem Res, 2000,25(2):303-312.
60. Behl C, Cole GM, Schubert D. Vitamin E protects nerve cells from amyloid β protein toxicity. Biochem Biophys Res Commun,1992,186(8):944-950.
61. Blusztajn JK. Berse B. The cholinergic neuronal phenotype in Alzheimer's disease. Metab Brain Dis,2000,15(3):45-64.
62. Abe E, Casamenti F, Giovannelli L, et al. Administration of amyloid β-peptides into the medial septum of rats decreases acetylcholine release from hippocampus in vivo. Brain Res,1994, 636 (1):162-164.
63. Harkany T, Lengyel Z, Soos K, Penke B, Luiten PG, Gulya Ket al. Cholinotoxic effects of P-amyloidl-42 peptide on cortical projections of the rat nucleus basalis magnocellularis. Brain Res,1995,695 (1):71-75.
64. Itoh A, Nitta A, Nadai M, et al. Dysfunction of cholinergic and dopaminergic neuronal systems in P-amyloid protein-infused rats. J Neurochem,1996,66(3):1113-1117.
65. Giovannelli L, Casamenti F, Scali C, et al. Differential effects of amyloid peptides β-(1-40) and β-(25-35) injections into rat nucleus basalis. Neuroscience 1995; 66(4):781-792.
66. Giovannini MG, Scali C, Prosperi C, et al. Beta-amyloid-induced inflammation and cholinergic hypofunction in the rat brain in vivo:involvement of the p38MAPK pathway. Neurobiol Dis,2002,11 (2):257-274.
67. Boncristiano S, Calhoun ME, Kelly PH, et al. Cholinergic changes in the APP23 transgenic mouse model of cerebral amyloidosis. J Neurosci,2002,22 (8):3234-3243.
68. Gau JT, Steinhilb ML, Kao TC, et al. Stable β-secretase activity and presynaptic cholinergic markers during progressive central nervous system amyloidogenesis in Tg2576 mice. Am J Pathol,2002,160(2):731-738.
69. Hardy J,Selkoe DJ, The amyloid hypothesis of Alzheimer's disease:Progress and problems on the road to theropeutics.science,2002,297 (5580):353-356.
70. Goate A., Chartier-Harlin M. C., Mullan M., et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature,1991,349(6311): 704-706.
71. Sherrington R., Rogaev E. I., Liang Y., et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease, Nature,1995,375(6534):754-760
72. Levy-Lahad, E., Wasco, W., Poorkaj, P., et al. Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science,1995,269(5226):973-977.
73. Rogaev E. I., Sherrington R., Rogaeva E. A., et al. Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene.Nature,1995,376(6543):775-778.
74. Lewis J, Dickson DW, Lin WL, Chisholm L, Corral A, Jones G, Yen SH, Sahara N, Skipper L, Yager D, Eckman C, Hardy J, Hutton M, McGowan E. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science,2001,293(5534): 1487-1491.
75. Mihaela N, Rakez K, Saskia M, et al.Small Molecule Inhibitors of Aggregation Indicate That Amyloid Oligomerization and Fibrillization Pathways Are Independent and Distinct. J Biolo Chem,2007,282(14):10311-10324.
76. Eckert GP, Wood WG, Muller WE. Cholesterol Modulates the Membrane-Disordering Effects of Beta-Amyloid Peptides in the Hippocampus:Specific Changes in Alzheimer's Disease. Demebtia,2000,11 (4):181-186.
77. Kawahara M. Disruption of calcium homeostasis in the pathogenesis of Alzheimer's disease and other conformational diseases. Curr. Alzheimer Res,2004,1 (2): 87-95.
78. Puglielli L, Friedlich AL, Setchell KD,et al. Alzheimer disease beta6amyloid activity mimics cholesterol oxidase. J Clin Invest,2005,115(9):2556-2563.
79. Butterfield D. A, Jennifer D, Chava P, et al. Evidence of oxidative damage in Alzheimer's disease brain:central role for amyloid beta-peptide. Trends Mol. Med,2001,7(12): 548-554.
80. Smith M A, Harris P L, Sayre LM et al. Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. Proc. Natl Acad. Sci. USA,1997,94 (18):9866-9868.
81. Blass JP. Brain metabolism and brain disease:is metabolic deficiency the proximate cause of Alzheimer dementia? J. Neurosci. Res,2001,66 (5):851-856.
82. Dodart JC, Chantal M, Kelly RB, et al. Early regional cerebral glucose hypometabolism in transgenic mice overexpressing the V717F beta-amyloid precursor protein. Neurosci. Lett,1999, 277 (1):49-52.
83. Cutler RG, Kelly J, Storie, K, et al. Involvment of perturbed ceramide and cholesterol metabolism in brain aging and Alzheimer's disease. Proc. Natl Acad. Sci. USA,2004, 101(7):2070-2075.
84. McGeer P. L, McGeer E. G. Local neuroinflammation and the progression of Alzheimer's disease.J. Neurovirol,2002,8(6):529-538.
85. Xu J, Shawei C, Hinan A, et al. Amyloid-beta peptides are cytotoxic to oligodendrocytes. J. Neurosci,2001,21(1):1-5.
86. Bard F, Cannon C, Barbour R, et al. Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nature Med,2002,6(8):916-919.
87. Jantzen PT., Connor KE, DiCarlo G, et al. Microglial activation and beta-amyloid deposit reduction caused by a nitric oxide-releasing nonsteroidal anti-inflammatory drug in amyloid precursor protein plus presenilin-1 transgenic mice. J. Neurosci,2002,22(6):2246-2254.
88. Amitabha Majumdar, Dana Cruz, Nikiya Asamoah, et al. Activation of Microglia Acidifies Lysosomes and Leads to Degradation of Alzheimer Amyloid Fibrils. Molecular Biology of the Cell,2007,18(4):1490-1496.
89. Simard A, Soulet D, Gowing G, et al. Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer's disease. Neuron,2006,49(4):489-502.
90. West MJ, Coleman PD, Flood DG, et al. Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer's disease. Lancet,1994,344(8925):769-772.
91. Eckert A, Uta K, Celio A, et al. Mitochondrial dysfunction, apoptotic cell death, and Alzheimer's disease. Biochem. Pharmacol,2003,66 (8):1627-1634.
92. Mandelkow EM, Stamer K; Vogel R, et al. Clogging of axons by tau, inhibition of axonal traffic and starvation of synapses. Neurobiol Aging,2003,24 (8):1079-1085.
93. 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 (3):409-421.
94. Farlow, M.. A clinical overview of cholinesterase inhibitors in Alzheimer's disease. Int. Psychogeriatr,2002,14 (1):93-126.
95. Cleary J.P. Naturaloligomers of the amyloid-beta protein specifically disrupt cognitive function. Nat Neurosci,2005,8(1):79-84.
96. Billings L.M. Intraneuronal Aβcauses the onset of early Alzheimer's disease-related cognitive deficits in transgenic mice. Neuron,2005,45(5):675-688.
97. Townsend M. Effects of secreted oligomers of amyloid beta-protein on hippocampal synaptic plasticity:a potent role for trimers. J. Physiol,2006,572(2):477-492.
98. S. Knafo, L. Alonso-Nanclares, J. Gonzalez-Soriano, P. Merino-Serrais,et al. Widespread Changes in Dendritic Spines in a Model of Alzheimer's Disease.Cereb Cortex, 2009,19(3):586-592.
99. J. Steven Jacobsen, Chi-Cheng Wu, Jeffrey M. Redwine, Thomas A. Comery, Robert Arias, Mark Bowlby, Robert Martone, John H. Morrison, Menelas N. Pangalos, Peter H. Reinhart, Floyd E. Bloom. Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer's disease.PNAS,2006,28,103(13):5161-5166.
100.Donna L. Moolman,Ottavio V. Vitolo,Jean-Paul G. Vonsattel,Michael L. Shelanski.Dendr ite and dendritic spine alterations in alzheimer models. Journal of Neurocytology,2004,33 (3):377-387.
1. A Fujise,K Mizuno, Y Ueda, S Osada, S Hirai, A Takayanagi, et al. Speciicity of the high afinity interaction of protein kinase C with a physiological substrate, myristoylated alanine-rich protein kinase C substrate. J Biol Chem,1994,16 (12):31642-31648.
2. Michael Glaser,Stephen Wanaski,Carolyn A. Buser,Valentina Boguslavsky,Wahid Rashidzada,Andrew Morris, et al.Myristoylated Alanine-rich C Kinase Substrate (MARCKS) Produces Reversible Inhibition of Phospholipase C by Sequestering Phosphatidylinositol 4,5-Bisphosphate in Lateral Domains. J Bio Chem,1996,271 (10):26187-26193.
3. A. Arbuzova, A.A. Schmitz, G. Vergeres, Cross-talk unfolded:MARCKS proteins. Biochem,2002,362(1):1-12.
4. Paul A. Janmey, Uno Lindberg. Cytoskeletal regulation:rich in lipids. Nat Rev Mol Cell Biol,2004,5(8):658-66.
5. Schmidt,A; Hall,MN. Signaling to the actin cytoskeleton. Annu Rev Cell Dev Biol, 1998,14 (11):305-308.
6. Janmey PA. Phosphoinositides and calcium as regulators of cellular actin assembly and disassembly. Annu. Rev. Physiol,1994,56 (11):169-191.
7. Anna Dunaevsky,Ayumu Tashiro,Ania Majewska,Carol Mason,Rafael Yuste.Developmental regulation of spine motility in the mammalian central nervous system.Proc. Natl. Acad. Sci. USA,1999,96(10):13438-13443.
8. Anthony J.G.D. Holtmaa, Joshua T. Trachtenberg, Linda Wilbrecht, Gordon M. Shepherd, Xiaoqun Zhang, Graham W. Knott, et al.Transient and persistent dendritic spines in the neocortex in vivo.Neuron,2005,45(2):279-291.
9. H. Hering, C.C. Lin, M. Sheng, Lipid rafts in the maintenance of synapses, dendritic spines, and surface, AMPA receptor stability. Neurosci,2003,23(8),3262-3271.
10. T.A. Blanpied, M.D. Ehlers, Microanatomy of dendritic spines:emerging principles of synaptic pathology in psychiatric and neurological disease. Biol. Psychiatry,2004,55(12): 1121-1127.
11. Kasai H.; Matsuzaki M.;Noguchi J.;Yasumatsu N.;Nakahara H. Structure-stability-function relationships of dendritic spines. Tren in Neurosci,2003, 26(7):360-368.
12. M.H. Monfils, G.C. Teskey, Induction of long-term depression is associated with decreased dendritic length and spine density in layers Ⅲ and Ⅴ of sensorimotor neocortex. Synapse,2004,53(12):14-121.
13. R.C. Malenka, M.F. Bear, LTP and LTD:an embarrassment of riches. Neuron,2004, 44(1):5-21.
14. S. Halpain, K. Spencer, S. Graber, Dynamics and pathology of dendritic spines. Prog. Brain Res,2005,147(1):29-37.
15. M. Matsuzaki, N. Honkura, G.C. Ellis-Davies, H. Kasai. Structural basis of long-term potentiation in single dendritic spines. Nature,2004,429(6):761-766.
16. U.V. Nagerl, N. Eberhorn, S.B. Cambridge, T. Bonhoeffer, Bidirectional activity-dependent morphological plasticity in hippocampal neurons. Neuron,2004, 44(5):759-767.
17. F.S. Sheu, B.J. McCabe, G. Horn,A. Routtenberg, Learning selectively increases protein kinase C substrate phorphorylation in specific regions of the chick brain.Proc. Natl. Acad. Sci. USA,1993,90 (4):2705-2709.
18. D.J. Stumpo, C.B. Bock, J.S. Tuttle, P.J. Blackshear, MARCKS deficiency in mice leads to abnormal brain development and perinatal death. Proc. Natl. Acad. Sci. USA,1995,92 (4):944-948.
19. R.K. McNamara, D.J. Stumpo, L.M. Morel. Effect of reduced myristoylated alanine-rich C kinase substrate expression on hippocampal mossy fiber development and spatial learning in mutant mice:transgenic rescue and interactions with gene background.Proc. Natl. Acad. Sci, 1998,95(24):14517-14522.
20. Robert K. McNamara, Rifat J. Hussain, Erica J. Simon. Effect of myristoylated alanine-rich C kinase substrate (MARCKS) overexpression on hippocampus-dependent learning and hippocampal synaptic plasticity in MARCKS transgenic mice.Hippocampus,2005, 15(5):675-683.
21. Calabrese, S. Halpain, Essential role for the PKC target MARCKS in maintaining dendritic spine morphology.Neuron,2005,48 (1):70-90.
22. M. Fischer, S. Kaech, U. Wagner, H. Brinkhaus, A. Matus, Glutamate receptors regulate actinbased plasticity in dendritic spines. Nat. Neurosci,2000,3 (9):887-894.
23. Korkotian E, Segal M.Spike-associated fast twitches of dendritic spines in cultured hippocampal neurons. Neuron,2001,30 (3):751-758.
24. Daniel L.Alkon,Miao-Kun Sun,Tomas J.Nelson. PKC signaling deficits:a mechanistic hypothesis for the origins of Alzheimer's disease. Tren Pharmaco Sci,2007,28(2):51-60.
25. Weinreb O, Bar-Am O, Amit T, Chillag-Talmor O, Youdim M. Neuroprotection via pro-survival protein-kinase C isoforms associated with Bcl-2 family members. FASEB J,2004,12 (9):1471-1473.
26. Cole G, Dobkins KR, Hansen LA, Terry RD, Saitoh T. Decreased levels of protein kinase C in Alzheimer brain. Brain Res 1988,452 (6):165-174.
27. Wang HY, Pisano MR, Friedman E. Attenuated protein kinase C activity and translocation in Alzheimer's disease brain. Neurobiol Aging,1994,15(3):293-298.
28. Battaini F, Pascale A, Lucchi L, Pasinetti GM, Govoni S. Protein kinase C anchoring deficit in postmortem brains of Alzheimer's disease patients. Exp Neurol,1999;159(10):559-564.
29. lariu A, Yamada K, Mamiya T, Hefco V, Nabeshima T. Memory impairment induced by chronic intracerebroventricular infusion of beta-amyloid (1-40) involves downregulation of protein kinase C. Brain Res,2002,957 (2):278-286.
30. Kimura, Takemi, Yamamoto, Hideyuki; Takamatsu, Junichi; Yuzuriha, Takefumi; Miyamoto, Eishichi; Miyakawa, Ta. Phosphorylation of MARCKS in Alzheimer disease brains. Neuroreport,2000, 11(4):869-873.
31. Hong-Qi Yang, Mao-Wen Ba, Ru-Jing Ren, Yu-Hong Zhang, Jian-Fang Ma, Jing Pan, Guo-Qiang Lu,Sheng-Di Chen.Mitogen activated protein kinase and protein kinase C activation mediate promotion of sAPP secretion by deprenyl. Neuroche Int,2007,50(1):74-82.
32. Tanimukai, Satoshi; Hasegawa, Hiroshi; Nakai,Masamichi;Yagi, Keiko; Hirai, Midori; Saito,Naoaki; Taniguchi, Taizo; Terashima, Akira;Yasuda, Minoru; Kawamata, Toshio; Tanaka, ChikakoCA.Nanomolar amyloid [beta] protein activates a specific PKC isoform mediating phosphorylation of MARCKS in Neuro2A cells. Neuroreport,2002,13(4):549-553.
33. Hasegawa, Hiroshi; Nakai, Masamichi; Tanimukai, Satoshi; Taniguchi, Taizo; Terashima, Akira; Kawamata, Toshio; Fukunaga, Kohji; Miyamoto, Eishichi; Misaki, Kazuyo; Mukai, Hideyuki; Tanaka, Chikako CA.Microglial signaling by amyloid [beta] protein through mitogen-activated protein kinase mediating phosphorylation of MARCKS. Neuroreport,2001, 12(11):2567-2571.
34.. Murphy, A., Sunohara, J.R., Sundaram, M. Induction of protein kinase C substrates, Myristoylated alanine-rich C kinase substrate (MARCKS) and MARCKS-related protein (MRP), by amyloid β-protein in mouse BV-2 microglial cells.Neuroscience Letters,2003,347(1):9-12.
1. Desai AK, Grossberg GT. Diagnosis and treatment of Alzheimer's disease. Neurology. 2005;64(12):34-39.
2. Doody RS, Winblad B, Jelic V. Memantine:a glutamate antagonist for treatment of Alzheimer's disease. New York:Martin Dunitz,2004:137-144.
3.陕西省中医研究院.医林改错注释.北京：人民卫生出版社,1985.12：38.
4.程国彭,医学心悟通解.西安：三秦出版社,2005：220.
5.汪昂.本草备要.上海：商务印书馆,1954：158.
6.张仲景.伤寒论.北京：中国中医药出版社,2006：97.
7.张景岳.景岳全书.太原：山西科学技术出版社,2006：385.
8.陈士铎.辨证录.北京：人民卫生出版社,1989：241.
9.刘岚.对“古代中国人寿命与人均粮食占有量”的质疑.人口研究.2002.26(2)：70-72.
10.刘鹏飞.中国步入人口老龄化社会的经济学思考.西北人口.2006.112(6)：24-26.
11.王永炎.关于提高脑血管疾病疗效难点的思考.中国中西医结合杂志,1997,17(2)：195-196.
12.唐启盛“浊毒痹阻脑络”对老年期痴呆的影响.北京中医药大学学报.1997,20(6)：24-25.
13. Mark P.Mattson. Pathways towards and away from Alzheimer's disease. Nature, 2004,430(5):631-639.
14.苏芮,韩振蕴,范吉平.基于“毒损脑络”理论的老年性痴呆中医病机探讨.南京中医药大学学报.2010,26(3)：93-94.
15.陆曦.痴呆的治疗.江苏中医药.2006,27(12)：3-4.
16.过伟峰.从“肾虚髓空、痰瘀闭阻脑络”论治老年痴呆.江苏中医药.2006.27(12)：6-7.
17.王永炎.老年性痴呆辨治.中国医药学报.1991.9(2)：49-51.
18.贾孟辉,贺晓惠,田建英.从阳虚论治老年性痴呆.新中医.2005.37(11)：80-81.
19.朱建华.老年性痴呆.江苏中医药.2004,25,(10)：13-14.
20.赵冰,张华东,张晨.谢海洲治疗老年性痴呆经验.中医杂志.2006.47(4)：258-259.
21.黄书慧.颜乾麟运用古方治疗老年性痴呆经验.中医杂志.2008.49(2)：112-113.
22.张大宁,张宗礼,车树强,等.补活抗衰老胶囊对30例老年痴呆氧自由基代谢的影响.陕西中医.2003.24(2)：120-122.
23.李晓辉,高萍.聪敏汤治疗老年痴呆30例.陕西中医.2006.27(5)：544-545.
24.华刚.地黄饮子加减治疗老年痴呆症26例.四川中医.2004.22(12)：36-37.
25.赵洪夫,李瑞云.老年性痴呆的中西医综合治疗.中西医结合心脑血管病杂志.2004,2(7)：427-428.
26.陈焕松,夏韶霞.化瘀醒脑汤治疗老年性痴呆58例.河北中医,2002,24(7)：502-503.
27.黎其才,王明全.中医治疗117例老年性痴呆临床体会.四川中医.2008.26(3)：61-62.
28.陈民,肖燕倩.夏翔治疗老年痴呆的经验.湖北中医杂志.1999.21(3)：102.
29.谢美玲.补肾活血化瘀法治疗老年性痴呆40例.新中医,1997,29(11)：60.
30.孙维广,廖慧丽,黄兆胜,等.老年性痴呆病病理与中药干预途径的探讨.中医药学刊.2001.19(4)：373-375.
31.杨文明,韩明向,李泽庚,等.豁痰化瘀中药复方对白介素-1 β诱导大鼠脑组织APPmRNA表达的影响.中国中西医结台急救杂志,2001,8(5)：278-270.
32.蔡永春,李凤文,张立石.补肾活血方对衰老小鼠学习记忆功能的影响.中国中医基础医学杂志,1998,17(3)：133-135.
33.兴桂华,牛英才,张晓杰,等.通络救脑口服液对老年性痴呆模型大鼠海马区生长抑素、胆碱乙酰化酶表达的影响.中华中医药杂志.2008.23(4)：364-366.
34.谢宁,何秀丽,周妍妍,等.地黄饮子对老年痴呆模型大鼠行为、AchE及Na +K+-ATP、 Ca2-ATP酶活性的影响.中医药学刊,2004,22(7)：1162-1163.
35.焦俊英,支江平,孙岩.醒脑增智方对AD模型大鼠脑组织神经细胞凋亡的影响.陕西中医.2005.26(10)：1114-1115.
36.肖柳英,潘竞锵,吴维城,等.加味当归芍药散对阿尔茨海默病模型小鼠记忆能力和脑组织tau蛋白及Fas抗原含量的影响.中医杂志,2004,45(5)：378-380.
37.尹宗宁.中医药防治老年痴呆症的研究进展.中国老年学杂志.2005.25(3)：354-355.
38.汪钟.丹参有效成分的研究进展.中国医学科学院学报,1999,16(2)：140-142.
39.周大兴,李昌煜,林乾良.石菖蒲对小鼠学习记忆的促进作用.中草药,1992,23(8)：417-419.
40.姚碧文,陈伟.银杏叶药理研究进展.浙江中西医结合杂志,2005,15(3)：192-193.
41.张旭静,曹奕丰,冯春红,等.川芎、当归对大鼠血栓形成的影响.中国临床药学杂志,2002,11(1)：45-47.
42.沈丽霞.蛇床子素对学习记忆的影响及其机制分析.中药学学报.1999.34(6)：405.
43.徐江平,杨雪梅.中草药活性成分防治阿尔采末病的研究进展.第一军医大学学报，2001,1(1)： 23.
1. Satyabrata Kar, Stephen P.M. Slowikowski, et al. Interactions between P-amyloid and central cholinergic neurons:implications for Alzheimer's disease Psychiatry Neurosci 2004; 29(6):427-441.
2. J.Poirier. Apolipoprotein E, cholesterol transport and synthesis in sporadic Alzheimer's disease. Neurobiology of Aging,2005,26(3):355-361.
3. Lambert, J.C., and Amouyel, P. Genetic heterogeneity of Alzheimer's disease:Complexity and advances. Psychoneuroendocrinology,2007,32(1):62-70.
4. George P, Charles W. The rat brain in stereotaxic coordinates. Third ed. Beijing:people' publishing house,2005.30-36.
5. Jesberger J. A, Richardson J. R., Animal models of depression:Parallels and correlates to severe depression in humans. Biological Psychiatry,1985,20(7):764-784.
6. Paul Willner. Behavioural Models in Psychopharmacology. Theoretical, Industrial and Clinical Perspectives Cambridge university press.1991:1-3.
7. Hardy J, Selkoe DJ, The amyloid hypothesis of Alzheimer's disease:Progress and problems on the road to theropeutics.science,2002,297(7):353-356.
8. Bondolfi L, Calhoun M, Ermini F, et al. Amyloid-associated neuron loss and gliogenesis in the neocortex of amyloid precursor protein transgenic mice. J Neurosci,2002,22(2):515-522.
9. Hsiao K, Chapman P, Nilsen S, et al. Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice. Science,1996,274(5284):99-102.
10. Calhoun M, Wiederhold K, Abramowski D, et al. Neuron loss in APP transgenic mice. Nature,1998,395(6704):755-756.
11. Itoh A, Nitta A, Nadai M, et al. Dysfunction of cholinergic and dopaminergic neuronal systems in P-amyloid protein-infused rats. J Neurochem,1996,66(3):1113-1117.
12. Giovannelli L, Casamenti F, Scali C, et al. Differential effects of amyloid peptides β-(1-40) and β-(25-35) injections into rat nucleus basalis. Neuroscience 1995; 66(4):781-792.
13. Harkany T, Lengyel Z, Soos K, et al. Cholinotoxic effects of β-amyloid 1-42 peptide on cortical projections of the rat nucleus basalis magnocellularis. Brain Res 1995; 695:71-75.
14. Lewis J, Dickson DW, Lin WL, et al. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science,2001,293(5534):1487-1491.
15. Bondolfi L, Calhoun M, Ermini F, et al. Amyloid-associated neuron loss and gliogenesis in the neocortex of amyloid precursor protein transgenic mice. J Neurosci,2002,22(2):515-522.
16. David H. E, Kenzie L. P, Jane S, et al.Toward a model of drug relapse:An assessment of the validity of the reinstatement procedure. Psychopharmacology.2006 November; 189(1):1-16.
17. Mohs RC. Memory impairment in amnesia and dementia:implications for the use of animal models. Neurobiol Aging,1988,9(5):465-468.
18. Braak, H. and Braak, E., Neuropathological staging of Alzheimer-related changes. Acta Neuropathologica,1991,82(4):239-259.
1.Reddy PH, Mani G, Park BS, et al. Differential loss of synaptic proteins in Alzheimer's disease:implications for synaptic dysfunction. J. Alzheimers Dis,2005,7 (2):103-117.
2. Arendt T. Alzheimer's disease as a disorder of mechanisms underlying structural brain self organization. Neuroscience,2001; 102(4):723-765.
3. Flavio K, Taisuke T, Helen H, et al. APP processing and synaptic function. Neuron, 2003,37,(6):925-937.
4. Gong Y, Chang L, Viola KL, et al. Alzheimer's disease-affected brain:presence of oligomeric A beta ligands (ADDLs) suggests a molecular basis for reversible memory loss. Proc Natl Acad Sci U S A,2003,100(8):10417-10422.
5. Oddo S. Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron.2003,39,(3):409-421.
6. Mattson. Pathways towards and away from Alzheimer's disease. Nature,2004, 430(5):631-639.
7. Arendt T. Neurodegeneration and plasticity. Int J Dev Neurosci,2004; 22(7):507-14.
8. Holtmaat A.J, Trachtenberg J.T, Wilbrecht L. et al. Transient and persistent dendritic spines in the neocortex in vivo. Neuron,2005,45(2):279-291.
9. Kasai H, Matsuzaki M, Noguchi J, et al. Structure stability function relationships of dendritic spines. Trends Neurosci,2003,26(7):360-368.
10. Arbuzova A, Schmitz A, Vergeres G, Cross-talk unfolded:MARCKS proteins. Biochem.J,2002,362(1):1-12.
11. Ferrer, I., Gullotta, F. Down's syndrome and Alzheimer's disease:dendritic spine counts in the hippocampus. Acta Neuropathol,1990,79(6):680-685.
12. Cleary J.P. Naturaloligomers of the amyloid-beta protein specifically disrupt cognitive function. Nat Neurosci,2005,8(1):79-84.
13. Billings L.M. Intraneuronal Aβcauses the onset of early Alzheimer's disease-related cognitive deficits in transgenic mice. Neuron,2005,45(5):675-688.
14. Townsend M. Effects of secreted oligomers of amyloid beta-protein on hippocampal synaptic plasticity:a potent role for trimers. J. Physiol,2006, 572(2):477-492.
15. Thorsten Laux, Kiyoko Fukami, Marcus Thelen,et al. GAP43, MARCKS, and CAP23 Modulate PI(4,5)P2 at Plasmalemmal Rafts, and Regulate Cell Cortex Actin Dynamics through a Common Mechanism. J Cell Biolo,2000,149(7):1455-1471.
16. Satyabrata Kar, Stephen P.M. Slowikowski, David Westaway, et al. Mount. Interactions between β-amyloid and central cholinergic neurons:implications for Alzheimer's disease Psychiatry. Neurosci,2004,29(6):427-441.
17. Doody RS, Winblad B, Jelic V. Memantine:a glutamate antagonist for treatment of Alzheimer's disease. Alzheimer's disease and related disorders annual 2004. New York:Martin Dunitz,2004:137-144.
18. R.K. McNamara, D.J. Stumpo, L.M. Morel, et al. Effect of reduced myristoylated alanine-rich C kinase substrate expression on hippocampal mossy fiber development and spatial learning in mutant mice:transgenic rescue and interactions with gene background, Proc.Natl.Acad.Sci,1998,95 (24):14517-14522.
19. Robert K. McNamara, Rifat J. Hussain, Erica J. Simon, et al. Effect of myristoylated alanine-rich C kinase substrate (MARCKS) overexpression on hippocampus-dependent learning and hippocampal synaptic plasticity in MARCKS transgenic mice.Hippocampus,2005,15(5):675-683.
20. D.J. Stumpo, C.B. Bock, J.S. Tuttle, P.J. Blackshear, MARCKS deficiency in mice leads to abnormal brain development and perinatal death. Proc. Natl. Acad. Sci. USA, 1995,92 (4):944-948.
21. R.K. McNamara, D.J. Stumpo, L.M. Morel. Effect of reduced myristoylated alanine-rich C kinase substrate expression on hippocampal mossy fiber development and spatial learning in mutant mice:transgenic rescue and interactions with gene background.Proc. Natl. Acad. Sci,1998,95 (24):14517-14522.
22. Calabrese B, Halpain S, Essential role for the PKC target MARCKS in maintaining dendritic spine morphology. Neuron,2005,48(1):7-90.
23. Sohn RH, Goldschmidt-Clermont PJ. Profilin:at the crossroads of signal transduction and the actin cytoskeleton. BioEssays,1994.16(5):465-472.
24. Bearer EL. Direct observation of actin filament severing by gelsolin and binding by Cap39 and CapZ. J. Cell Biol,1991,115(12):1629-1638.
25. Schmidt,A; Hall,MN. Signaling to the actin cytoskeleton. Annu Rev Cell Dev Biol,1998,14 (11):305-308.
26. Harris KM, Stevens JK. Dendritic spines of CA 1 pyramidal cells in the rat hippocampus:serial electron microscopy with reference to their biophysical characteristics. J Neurosci,1989,9(8):2982-2997.
27. Ferrer I, Gullotta F. Down's syndrome and Alzheimer's disease:dendritic spine counts in the hippocampus. Acta Neuropathol,1990,79(6):680-685.
28. Takahashi H, Sekino Y, Tanaka S, et al. Drebrin-dependent actin clustering in dendritic filopodia governs synaptic targeting of postsynaptic density-95 and dendritic spine morphogenesis. J. Neurosci.2003,23(16):6586-6595.
29. Shirao T.The roles of microfilament-associated proteins, drebrins, in brain morphogenesis:a review. J Biochem,1995,117(2):231-236.
30. Xin-peng Dun, John K. Chilton.Control of cell shape and plasticity during development and disease by the actin-binding protein Drebrin. Histol Histopathol 2010, 25(10):533-540.
31. Fukazawa Y, Saitoh Y, Ozawa F, Ohta Y, Mizuno K, et al. Hippocampal LTP is accompanied by enhanced F-actin content within the dendritic spine that is essential for late LTP maintenance in vivo. Neuron 2003; 38(3):447-460.
32. Kobayashi R, Sekino Y, Shirao T, et al. Antisense knockdown of drebrin A, a dendritic spine protein, causes stronger preference, impaired pre-pulse inhibition, and an increased sensitivity to psychostimulant. Neurosci Res 2004; 49(2):205-217.
33. Takahashi H, Mizui T, Shirao T. Downregulation of drebrin A expression suppresses synaptic targeting of NMDA receptors in developing hippocampal neurones. J Neurochem 2006; 97(1):110-105.
34. Takahashi H., Yamazaki H., Hanamura K., et al. Activity of the AMPA receptor regulates drebrin stabilization in dendritic spine morphogenesis. J. Cell Sci,2009, 122(4):1211-1219.
35. Sekino Y, Tanaka S, Hanamura, K, et al. Activation of N-methyl-D-aspartate receptor induces a shift of drebrindistribution:disappearance from dendritic spines and appearance in dendritic shafts. Mol.Cell. Neurosci,2006,31 (13):493-504.
36. Hatanpaa K, Isaacs KR, Shirao T, et al. Loss of proteins regulating synaptic plasticity in normal aging of the human brain and in Alzheimer disease. J Neuropathol Exp Neurol 1999; 58(6):637-643.
37. Calon F., Lim G.P., Yang F., et al. Docosahexaenoic acid protects from dendritic pathology in an Alzheimer's disease mouse model. Neuron,2004,43(5):633-645.
38. Zhao L., Ma Q.L., Calon F.,et al. Role of p21-activated kinase pathway defects in the cognitive deficits of Alzheimer disease. Nat. Neurosci,2006,9(2):234-242.
39. Harigaya Y, Shoji M, Shirao T, Hirai S. Disappearance of actin-binding protein, drebrin, from hippocampal synapses in Alzheimer's disease. J Neurosci Res,1996, 43(1):87-92.
40. Kojima N, Shirao T. Synaptic dysfunction and disruption of postsynaptic drebrin-actin complex:a study of neurological disorders accompanied by cognitive deficits. Neurosci Res 2007; 58(1):1-5.
1.刘岚.对“古代中国人寿命与人均粮食占有量”的质疑.人口研究.2002.26(2)：70-72.
2.刘鹏飞.中国步入人口老龄化社会的经济学思考.西北人口.2006.112(6)：24-26.
3. 王永炎.关于提高脑血管疾病疗效难点的思考.中国中西医结合杂志,1997,17(2)：195-196.
4.唐启盛“浊毒痹阻脑络”对老年期痴呆的影响.北京中医药大学学报.1997,20(6)：24-25.
5. 王永炎,常富业,杨宝琴,病络与络病对比研究.北京中医药大学学报.28(3)：1-6.