神经变性过程中钙稳态变化与氧化应激初步研究
|
摘要
钙离子对神经元发挥基本功能起关键作用,包括对轴突生长和突触发生的调节、突触传递与可塑性以及细胞存活,但是过高的胞内钙水平对细胞是有害的。在人的衰老过程中,尤其在神经变性疾病病理过程中,细胞内钙调节系统失常可导致突触机能障碍、神经可塑性受损和产生氧化应激,从而导致神经元变性和凋亡。氧化应激可导致机体能量代谢异常和疾病相关蛋白的聚集,这反过来又影响钙稳态,它能通过钙离子通道的开启引发胞外钙内流和内质网的钙释放。年龄依赖性的神经元机能衰退与细胞膜上、内质网和线粒体中钙调相关蛋白的改变有着紧密的联系。衰老对神经元钙调节的损害程度与遗传因素和环境因素有关。深入了解衰老过程中氧化应激和钙稳态失调的细胞和分子机制,对人们最终找到治疗诸如阿尔茨海默、帕金森等神经退行性疾病的新方法有重要意义。
1.钙稳态变化与氧化应激作用关系的研究
为了研究氧化应激对钙稳态的影响,我们使用SH-SY5Y细胞及H_2O_2建立氧化应激模型,用Fluo-4钙离子荧光染料和Flexstation转液式荧光检测系统检测钙流的变化。结果发现H_2O_2可以诱导SH-SY5Y细胞钙离子内流以及内钙库钙离子的释放,钙流的大小与H_2O_2的浓度成正比;这种由氧化应激诱导的胞内钙稳态变化可在抗氧化剂L-抗坏血酸(维生素C)存存时得以缓解和改善。另外,对本所在研的姜黄素(CCM)及其一个结构衍生物(CCM-2)的研究表明,它们可以在保护细胞减轻氧化应激引起的损伤的同时,显著抑制H_2O_2诱导的钙流变化;而EUK4010则对氧化应激引起的钙流没有明显的抑制作用。
2.PS敲除AD模型小鼠氧化应激状态研究
早老素1(PS1)和早老素2(PS2)前脑条件性双敲除的阿尔茨海默病模型鼠,没有Aβ沉积,但却表现出认知能力减退、大脑萎缩、脑室扩大等神经退行性病变。氧化应激一直被认为在Aβ沉积的AD病理过程中起着重要作用,但是其在PS功能缺失诱导的AD中的机理尚未阐明,而PS蛋白在细胞内质网形成钙离子泄漏通道,同时钙离子水平的升高也可以间接产生氧化应激,所以为了了解氧化应激机制在PS功能缺失导致的AD模型中的病理作用,我们研究了4、8、12、16月龄的PS cDKO、PS1 cKO、PS2 KO小鼠与同年龄同性别的正常小鼠大脑皮层、海马和血浆中iPF_(2α)-Ⅲ(脂质过氧化指标)水平。结果表明PS敲除小鼠皮层、海马和血浆中iPF_(2α)-Ⅲ水平有显著升高,且变化呈现性别差异和年龄依赖性,PS cDKO小鼠iPF_(2α)-Ⅲ增高水平与单敲小鼠iPF_(2α)-Ⅲ增高水平显著相关,提示PS1、PS2都参与了氧化应激的产生。另外,在对12月龄的小鼠皮层和海马的α亚型钙/钙调蛋白依赖性蛋白激酶Ⅱ(α-CaMKII)的免疫印迹分析中发现PS cDKO小鼠的α-CaMKII表达有明显上调,其诱因可能与该基因型小鼠体内钙稳态失调有关,此结果与AD致病机理中的钙离子假说相一致。以上结果提示氧化应激,钙稳态失调以及它们的作用关系在PS功能缺失AD的病理变化过程中扮演者重要的角色。
3.EUK4010对PS cDKO小鼠脂质过氧化的抑制作用研究
EUK4010作为一种中药提取物中筛选出的天然酮类单体化合物。本研究所前期的研究发现该化合物对Aβ诱导的神经元凋亡有明显的抑制作用。为进一步了解EUK4010是否与PS cDKO小鼠神经变性的氧化应激病理学机理有关,本研究测定分析了喂食6个月EUK4010的6月龄cDKO小鼠大脑皮层和血浆中iPF_(2α)-Ⅲ水平,发现EUK4010对cDKO小鼠体内氧化应激状态无显著改善作用,提示其抑制Aβ诱导的神经元凋亡的作用可能与氧化应激通路无关。
Calcium(Ca~(2+))plays critical role in fundamental functions of neurons,from the regulation of neurite outgrowth,synaptogenesis,synaptic transmission and plasticity to cell survival.Although it is essential for neurons,excessively high level of intracellular Ca~(2+)is toxic to the cell.During aging,and especially in neurodegenerative disorders,cellular Ca~(2+)homeostasis is interrupted,which leads to synaptic dysfunction,impaired plasticity and oxidative stress.All these factors contribute to neuronal degeneration and apoptosis.Oxidative stress,resulting in metabolic disorder of energy and aggregation of disease-related proteins,adversely affect Ca~(2+)homeostasis in return.It causes Ca~(2+)fluxes into the cytoplasm from the extracelluar environment and from the endoplasmic reticulum through the Ca~(2+) channels.Alterations of Ca~(2+)-regulating proteins in the plasma membrane, endoplasmic reticulum,and mitochondria are involved in age-related neurodegeneration.The harm of aging on neuronal Ca~(2+)regulation are subject to genetic and environmental factors that may cause or affect the risk of neurodegenerative disease.A good understanding of the cellular and molecular mechanisms of oxidative stress and cellular Ca~(2+)dyshomeostasis during aging may be helpful to find novel therapies in neurological disorders such as Alzheimer's and Parkinson's diseases.
1.The Relationship of Calcium Homeostasis and Oxidative Stress in Vitro
To investigate the influence of oxidative stress on the calcium homeostasis,we used a model of oxidative stress on SH-SY5Y cells with H_2O_2.Fluo-4 calcium indicator and Flexstation were used to detect intracellular calcium flux.As a result, H_2O_2 caused Ca~(2+)influx into the cytoplasm from the extracellular environment and from the endoplasmic reticulum(ER),depending on the concentration of H_2O_2.And L-ascorbic acid was proved of being effective to reduce the Ca~(2+)influx caused by H_2O_2.Synthesized curcumin(CCM)and one of its derivatives(CCM-2)were studied as well.The results showed that these compounds could significantly protect the cells from intracellular Ca~(2+)increase caused by H_2O_2,while another natural compound, EUK4010,was demonstrated to have no such effect on Ca~(2+)homeostasis.
2.Oxidative Stress in PS Knockout Mouse Model of AD
Forebrain-specific and conditional presenilin-1(PS1)and presenilin-2(PS2) double knock-out mouse exhibits some usual hallmarks of Alzheimer's disease(AD), such as progressive memory dysfunction,forebrain degeneration and ventricle enlargemen,without the accumulation of Aβ.Oxidative stress mechanism has been long implicated predominantly in amyloidosis-mediated AD pathologies;however,its role in the pathogenic mechanism of loss-of-function of PS in AD remains unclear.It is believed that presenilins form ER Ca~(2+)leak channels and elevated Ca~(2+)levels in the cytoplasm can also indirectly cause oxidative stress.To identify and understand oxidative imbalance as an important mechanism of AD in response to PS loss-of-function,we examined oxidative stress status,using F_2-isoprostanes(iPF_(2α)-Ⅲ) as the marker of lipid peroxidation in vivo,in both brain tissues and circulation of 4-, 8-,12-,and 16-month PS cDKO,PS1 cKO,PS2 KO and the age-,gender-matched wide-type control mice(WT).Enhanced lipid peroxidation was occurred in a genderand age-related manner in PS KO mice,and the enhancement of iPF_(2α)-Ⅲin PS cDKO mice are dependent on both PS1 and PS2 deficiency.Western blot analysis of a-CaMKII revealed a significant increase of this protein in the brain of 12-month-old PS cDKO mice,implicating an involvement of calcium dyshomeostasis in the PS loss-of-function mechanism.In conclusion,the interaction of oxidative stree and calcium dyshomeostasis might have important role in response to the loss-of-function of PS in AD pathogenesis.
3.The Effect of EUK4010 on Lipid Peroxidation in PS cDKO mice
EUK4010 is a natural compound isolated from a herb,which has been used frequently in China for the treatment of cardiovascular diseases.EUK4010 has been identified to exhibit an inhibitory effect on beta-amyloid(Aβ)-induced loss of neuronal cell viability.To investigate if there is an anti-oxidative mechanism for EUK4010 in protecting neurons from neurodegeneration in PS cDKO mice,we administrated the 6-month-old PS cDKO mice with EUK4010 for 6 months and iPF_(2α)-Ⅲwas detected in both cerebral cortex and circulation after treatment.The results showed that there was no significant difference in production of iPF_(2α)-Ⅲbetween the EUK4010-treated animals and their controls,suggesting that neuronal pharmacological protecting role of EUK4010 might be not oxidative stress-related.
1.钙稳态变化与氧化应激作用关系的研究
为了研究氧化应激对钙稳态的影响,我们使用SH-SY5Y细胞及H_2O_2建立氧化应激模型,用Fluo-4钙离子荧光染料和Flexstation转液式荧光检测系统检测钙流的变化。结果发现H_2O_2可以诱导SH-SY5Y细胞钙离子内流以及内钙库钙离子的释放,钙流的大小与H_2O_2的浓度成正比;这种由氧化应激诱导的胞内钙稳态变化可在抗氧化剂L-抗坏血酸(维生素C)存存时得以缓解和改善。另外,对本所在研的姜黄素(CCM)及其一个结构衍生物(CCM-2)的研究表明,它们可以在保护细胞减轻氧化应激引起的损伤的同时,显著抑制H_2O_2诱导的钙流变化;而EUK4010则对氧化应激引起的钙流没有明显的抑制作用。
2.PS敲除AD模型小鼠氧化应激状态研究
早老素1(PS1)和早老素2(PS2)前脑条件性双敲除的阿尔茨海默病模型鼠,没有Aβ沉积,但却表现出认知能力减退、大脑萎缩、脑室扩大等神经退行性病变。氧化应激一直被认为在Aβ沉积的AD病理过程中起着重要作用,但是其在PS功能缺失诱导的AD中的机理尚未阐明,而PS蛋白在细胞内质网形成钙离子泄漏通道,同时钙离子水平的升高也可以间接产生氧化应激,所以为了了解氧化应激机制在PS功能缺失导致的AD模型中的病理作用,我们研究了4、8、12、16月龄的PS cDKO、PS1 cKO、PS2 KO小鼠与同年龄同性别的正常小鼠大脑皮层、海马和血浆中iPF_(2α)-Ⅲ(脂质过氧化指标)水平。结果表明PS敲除小鼠皮层、海马和血浆中iPF_(2α)-Ⅲ水平有显著升高,且变化呈现性别差异和年龄依赖性,PS cDKO小鼠iPF_(2α)-Ⅲ增高水平与单敲小鼠iPF_(2α)-Ⅲ增高水平显著相关,提示PS1、PS2都参与了氧化应激的产生。另外,在对12月龄的小鼠皮层和海马的α亚型钙/钙调蛋白依赖性蛋白激酶Ⅱ(α-CaMKII)的免疫印迹分析中发现PS cDKO小鼠的α-CaMKII表达有明显上调,其诱因可能与该基因型小鼠体内钙稳态失调有关,此结果与AD致病机理中的钙离子假说相一致。以上结果提示氧化应激,钙稳态失调以及它们的作用关系在PS功能缺失AD的病理变化过程中扮演者重要的角色。
3.EUK4010对PS cDKO小鼠脂质过氧化的抑制作用研究
EUK4010作为一种中药提取物中筛选出的天然酮类单体化合物。本研究所前期的研究发现该化合物对Aβ诱导的神经元凋亡有明显的抑制作用。为进一步了解EUK4010是否与PS cDKO小鼠神经变性的氧化应激病理学机理有关,本研究测定分析了喂食6个月EUK4010的6月龄cDKO小鼠大脑皮层和血浆中iPF_(2α)-Ⅲ水平,发现EUK4010对cDKO小鼠体内氧化应激状态无显著改善作用,提示其抑制Aβ诱导的神经元凋亡的作用可能与氧化应激通路无关。
Calcium(Ca~(2+))plays critical role in fundamental functions of neurons,from the regulation of neurite outgrowth,synaptogenesis,synaptic transmission and plasticity to cell survival.Although it is essential for neurons,excessively high level of intracellular Ca~(2+)is toxic to the cell.During aging,and especially in neurodegenerative disorders,cellular Ca~(2+)homeostasis is interrupted,which leads to synaptic dysfunction,impaired plasticity and oxidative stress.All these factors contribute to neuronal degeneration and apoptosis.Oxidative stress,resulting in metabolic disorder of energy and aggregation of disease-related proteins,adversely affect Ca~(2+)homeostasis in return.It causes Ca~(2+)fluxes into the cytoplasm from the extracelluar environment and from the endoplasmic reticulum through the Ca~(2+) channels.Alterations of Ca~(2+)-regulating proteins in the plasma membrane, endoplasmic reticulum,and mitochondria are involved in age-related neurodegeneration.The harm of aging on neuronal Ca~(2+)regulation are subject to genetic and environmental factors that may cause or affect the risk of neurodegenerative disease.A good understanding of the cellular and molecular mechanisms of oxidative stress and cellular Ca~(2+)dyshomeostasis during aging may be helpful to find novel therapies in neurological disorders such as Alzheimer's and Parkinson's diseases.
1.The Relationship of Calcium Homeostasis and Oxidative Stress in Vitro
To investigate the influence of oxidative stress on the calcium homeostasis,we used a model of oxidative stress on SH-SY5Y cells with H_2O_2.Fluo-4 calcium indicator and Flexstation were used to detect intracellular calcium flux.As a result, H_2O_2 caused Ca~(2+)influx into the cytoplasm from the extracellular environment and from the endoplasmic reticulum(ER),depending on the concentration of H_2O_2.And L-ascorbic acid was proved of being effective to reduce the Ca~(2+)influx caused by H_2O_2.Synthesized curcumin(CCM)and one of its derivatives(CCM-2)were studied as well.The results showed that these compounds could significantly protect the cells from intracellular Ca~(2+)increase caused by H_2O_2,while another natural compound, EUK4010,was demonstrated to have no such effect on Ca~(2+)homeostasis.
2.Oxidative Stress in PS Knockout Mouse Model of AD
Forebrain-specific and conditional presenilin-1(PS1)and presenilin-2(PS2) double knock-out mouse exhibits some usual hallmarks of Alzheimer's disease(AD), such as progressive memory dysfunction,forebrain degeneration and ventricle enlargemen,without the accumulation of Aβ.Oxidative stress mechanism has been long implicated predominantly in amyloidosis-mediated AD pathologies;however,its role in the pathogenic mechanism of loss-of-function of PS in AD remains unclear.It is believed that presenilins form ER Ca~(2+)leak channels and elevated Ca~(2+)levels in the cytoplasm can also indirectly cause oxidative stress.To identify and understand oxidative imbalance as an important mechanism of AD in response to PS loss-of-function,we examined oxidative stress status,using F_2-isoprostanes(iPF_(2α)-Ⅲ) as the marker of lipid peroxidation in vivo,in both brain tissues and circulation of 4-, 8-,12-,and 16-month PS cDKO,PS1 cKO,PS2 KO and the age-,gender-matched wide-type control mice(WT).Enhanced lipid peroxidation was occurred in a genderand age-related manner in PS KO mice,and the enhancement of iPF_(2α)-Ⅲin PS cDKO mice are dependent on both PS1 and PS2 deficiency.Western blot analysis of a-CaMKII revealed a significant increase of this protein in the brain of 12-month-old PS cDKO mice,implicating an involvement of calcium dyshomeostasis in the PS loss-of-function mechanism.In conclusion,the interaction of oxidative stree and calcium dyshomeostasis might have important role in response to the loss-of-function of PS in AD pathogenesis.
3.The Effect of EUK4010 on Lipid Peroxidation in PS cDKO mice
EUK4010 is a natural compound isolated from a herb,which has been used frequently in China for the treatment of cardiovascular diseases.EUK4010 has been identified to exhibit an inhibitory effect on beta-amyloid(Aβ)-induced loss of neuronal cell viability.To investigate if there is an anti-oxidative mechanism for EUK4010 in protecting neurons from neurodegeneration in PS cDKO mice,we administrated the 6-month-old PS cDKO mice with EUK4010 for 6 months and iPF_(2α)-Ⅲwas detected in both cerebral cortex and circulation after treatment.The results showed that there was no significant difference in production of iPF_(2α)-Ⅲbetween the EUK4010-treated animals and their controls,suggesting that neuronal pharmacological protecting role of EUK4010 might be not oxidative stress-related.
引文
1.Yuste,R.,A.Majewska,and K.Holthoff,From form to function:calcium compartmentalization in dendritic spines.Nat Neurosci,2000.3(7):p.653-9.
2.Chan,S.L.and M.R Mattson,Caspase and calpain substrates:roles in synaptic plasticity and cell death.J Neurosci Res,1999.58(1):p.167-90.
3.Nixon,R.A.,The calpains in aging and aging-related diseases.Ageing Res Rev,2003.2(4):p.407-18.
4.Leist,M.,et al.,Peroxynitrite and nitric oxide donors induce neuronal apoptosis by eliciting autocrine excitotoxicity.Eur J Neurosci,1997.9(7):p.1488-98.
5.Stefanis,L.,Caspase-dependent and-independent neuronal death:two distinct pathways to neuronal injury.Neuroscientist,2005.11(1):p.50-62.
6.Lafon-Cazal,M.,et al.,NMDA-dependent superoxide production and neurotoxicity.Nature,1993.364(6437):p.535-7.
7.Mattson,M.P.and M.Sherman,Perturbed signal transduction in neurodegenerative disorders involving aberrant protein aggregation.Neuromolecular Med,2003.4(1-2):p.109-32.
8.Gibson,G.E.,Interactions of oxidative stress with cellular calcium dynamics and glucose metabolism in Alzheimer's disease.Free Radic Biol Med,2002.32(11):p.1061-70.
9.Qin,S.,E.R.Stadtman,and P.B.Chock,Regulation of oxidative stress-induced calcium release by phosphatidylinositol 3-kinase and Bruton's tyrosine kinase in B cells.Proc Natl Acad Sci USA,2000.97(13):p.7118-23.
10.Zhao,Z.,et al.,One-step solid-phase extraction procedure for F(2)-isoprostanes.Clin Chem,2001.47(7):p.1306-8.
11.Berridge,M.J.,M.D.Bootman,and P.Lipp,Calcium--a life and death signal.Nature,1998.395(6703):p.645-8.
12.Marin,J.,et al.,Mechanisms involved in the cellular calcium homeostasis in vascular smooth muscle:calcium pumps.Life Sci,1999.64(5):p.279-303.
13.Halliwell,B.,Oxygen radicals as key mediators in neurological disease:fact or fiction? Ann Neurol,1992.32 Suppl:p.S10-5.
14.Suh,Y.H.and F.Checler,Amyloid precursor protein,presenilins,and alpha-synuclein:molecular pathogenesis and pharmacological applications in Alzheimer's disease.Pharmacol Rev,2002.54(3):p.469-525.
15.Hardy,J.A.and GA.Higgins,Alzheimer's disease:the amyloid cascade hypothesis.Science,1992.256(5054):p.184-5.
16.Hardy,J.and D.J.Selkoe,The amyloid hypothesis of Alzheimer's disease:progress and problems on the road to therapeutics.Science,2002.297(5580):p.353-6.
17.Stutzmann,G.E.,et al.,Enhanced ryanodine receptor recruitment contributes to Ca2+disruptions in young,adult,and aged Alzheimer's disease mice.J Neurosci,2006.26(19):p.5180-9.
18.Fortini,M.E.,Neurobiology:double trouble for neurons.Nature,2003.425(6958):p.565-6.
19.Wilquet,V.and B.De Strooper,Amyloid-beta precursor protein processing in neurodegeneration.Curr Opin Neurobiol,2004.14(5):p.582-8.
20.Campion,D.,et al.,Mutations of the presenilin I gene in families with early-onset Alzheimer's disease.Hum Mol Genet,1995.4(12):p.2373-7.
21.Shen,J.,et al.,Skeletal and CNS defects in Presenilin-1-deficient mice.Cell,1997.89(4):p.629-39.
22.Wong,P.C.,et al.,Presenilin 1 is required for Notchl and Dill expression in the paraxial mesoderm.Nature,1997.387(6630):p.288-92.
23.Feng,R.,et al.,Forebrain degeneration and ventricle enlargement caused by double knockout of Alzheimer's presenilin-1 and presenilin-2.Proc Natl Acad Sci USA,2004.101(21):p.8162-7.
24.Pratico,D.,et al.,Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer amyloidosis.J Neurosci,2001.21(12):p.4183-7.
25.Donoviel,D.B.,et al.,Mice lacking both presenilin genes exhibit early embryonic patterning defects.Genes Dev,1999.13(21):p.2801-10.
26.Steiner,H.,et al.,A loss of function mutation of presenilin-2 interferes with amyloid beta-peptide production and notch signaling.J Biol Chem,1999.274(40):p.28669-73.
27.Lai,M.T.,et al.,Presenilin-1 and presenilin-2 exhibit distinct yet overlapping gamma-secretase activities.J Biol Chem,2003.278(25):p.22475-81.
28.Montine,T.J.,et al.,Lipid peroxidation in aging brain and Alzheimer's disease.Free Radic Biol Med,2002.33(5):p.620-6.
29.Tamagno,E.,et al.,Oxidative stress activates a positive feedback between the gamma-and beta-secretase cleavages of the beta-amyloid precursor protein.J Neurochem,2008.104(3):p.683-95.
30.Hwang,E.S.and G.H.Kim,Biomarkers for oxidative stress status of DNA,lipids,and proteins in vitro and in vivo cancer research.Toxicology,2007.229(1-2):p.1-10.
31.Tamagno,E.,et al.,The various aggregation states of beta-amyloid 1-42 mediate different effects on oxidative stress,neurodegeneration,and BACE-1 expression.Free Radic Biol Med,2006.41(2):p.202-12.
32.Beal,M.F.,Oxidative damage as an early marker of Alzheimer's disease and mild cognitive impairment.Neurobiol Aging,2005.26(5):p.585-6.
33.Keller,J.N.,et al.,Evidence of increased oxidative damage in subjects with mild cognitive impairment.Neurology,2005.64(7):p.1152-6.
34.Lovell,M.A.and W.R.Markesbery,Oxidative damage in mild cognitive impairment and early Alzheimer's disease.J Neurosci Res,2007.85(14):p.3036-40.
35.Arlt,S.,U.Beisiegel,and A.KontUsh,Lipid peroxidation in neurodegeneration:new insights into Alzheimer's disease.Curr Opin Lipidol,2002.13(3):p.289-94.
36.Butterfield,D.A.,M.Perluigi,and R.Sultana,Oxidative stress in Alzheimer's disease brain:new insights from redox proteomics.Eur J Pharmacol,2006.545(1):p.39-50.
37.Volkel,W.,et al.,Increased brain levels of 4-hydroxy-2-nonenal glutathione conjugates in severe Alzheimer's disease.Neurochem Int,2006.48(8):p.679-86.
38.Wang,J.,W.R.Markesbery,and M.A.Lovell,Increased oxidative damage in nuclear and mitochondrial DNA in mild cognitive impairment.J Neurochem,2006.96(3):p.825-32.
39.Cecchi,C,et al.,Oxidative stress and reduced antioxidant defenses in peripheral cells from familial Alzheimer's patients.Free Radic Biol Med,2002.33(10):p.1372-9.
40.Migliore,L.,et al.,Oxidative DNA damage in peripheral leukocytes of mild cognitive impairment and AD patients.Neurobiol Aging,2005.26(5):p.567-73.
41.Chauhan,V.and A.Chauhan,Oxidative stress in Alzheimer's disease.Pathophysiology,2006.13(3):p.195-208.
42.Tu,H.,et al.,Presenilins form ER Ca2+leak channels,a function disrupted by familial Alzheimer's disease-linked mutations.Cell,2006.126(5):p.981-93.
43.Musiek,E.S.,et al.,Quantification of F-ring isoprostane-like compounds (F4-neuroprostanes) derived from docosahexaenoic acid in vivo in humans by a stable isotope dilution mass spectrometric assay.J Chromatogr B Analyt Technol Biomed Life Sci,2004.799(1):p.95-102.
44.De Strooper,B.,Loss-of-function presenilin mutations in Alzheimer disease.Talking Point on the role of presenilin mutations in Alzheimer disease.EMBO Rep,2007.8(2):p.141-6.
45.Saura,C.A.,et al.,Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration.Neuron,2004.42(1):p.23-36.
46.Turner,R.S.,Alzheimer's Disease in Man and Transgenic Mice :Females at Higher Risk.Am J Pathol,2001.158(3):p.797-801.
47.Yao,J.,et al.,Aging,gender and APOE isotype modulate metabolism of Alzheimer's Abeta peptides and F-isoprostanes in the absence of detectable amyloid deposits.J Neurochem,2004.90(4):p.1011-8.
48.Vina,J.,et al.,Effect of gender on mitochondrial toxicity of Alzheimer's Abeta peptide.Antioxid Redox Signal,2007.9(10):p.1677-90.
49.Candore,G,et al.,Age-related inflammatory diseases:role of genetics and gender in the pathophysiology of Alzheimer's disease.Ann N Y Acad Sci,2006.1089:p.472-86.
50.Guo,Q.,et al.,Alzheimer's PS-1 mutation perturbs calcium homeostasis and sensitizes PC 12 cells to death induced by amyloid beta-peptide.Neuroreport,1996.8(1):p.379-83.
51.Leissring,M.A.,et al.,Capacitative calcium entry deficits and elevated luminal calcium content in mutant presenilin-1 knockin mice.J Cell Biol, 2000.149(4):p.793-8.
52.Leissring,M.A.,et al.,Alzheimer's presenilin-1 mutation potentiates inositol 1,4,5-trisphosphate-mediated calcium signaling in Xenopus oocytes.J Neurochem,1999.72(3):p.1061-8.
53.Leissring,M.A.,I.Parker,and F.M.LaFerla,Presenilin-2 mutations modulate amplitude and kinetics of inositol 1,4,5-trisphosphate-mediated calcium signals.J Biol Chem,1999.274(46):p.32535-8.
54.Leissring,M.A.,et al.,A physiologic signaling role for the gamma-secretase-derived intracellular fragment of APR Proc Natl Acad Sci USA,2002.99(7):p.4697-702.
55.Nelson,O.,et al.,Familial Alzheimer disease-linked mutations specifically disrupt Ca2+leak function of presenilin 1.J Clin Invest,2007.117(5):p.1230-9.
56.Yang,Y.and D.G Cook,Presenilin-1 deficiency impairs glutamate-evoked intracellular calcium responses in neurons.Neuroscience,2004.124(3):p.501-5.
57.Zatti,G,et al.,Presenilin mutations linked to familial Alzheimer's disease reduce endoplasmic reticulum and Golgi apparatus calcium levels.Cell Calcium,2006.39(6):p.539-50.
58.Herms,J.,et al.,Capacitive calcium entry is directly attenuated by mutant presenilin-1,independent of the expression of the amyloid precursor protein.J Biol Chem,2003.278(4):p.2484-9.
59.Xie,L.H.,et al.,Oxidative-stress-induced afterdepolarizations and calmodulin kinase Ⅱ signaling.Circ Res,2009.104(1):p.79-86.
60.Griffith,L.C.,CaMKⅡ:new tricks for an old dog.Cell,2008.133(3):p.397-9.
61.Malenka,R.C.,et al.,An essential role for postsynaptic calmodulin and protein kinase activity in long-term potentiation.Nature,1989.340(6234):p.554-7.
62.Miller,P.,et al.,The stability of a stochastic CaMKⅡ switch:dependence on the number of enzyme molecules and protein turnover.PLoS Biol,2005.3(4):p.el07.
63.Liwen Sun,L.W.,Yong Sun,Syao-wei Tang and Yinghe Hu,Protective effects of EUK4010 on b-amyloid(l-42) induced degeneration of neuronal cells.European Journal of Neuroscience,2006.24:p.1011-1019.
64.Hanson,C.J.,M.D.Bootman,and H.L.Roderick,Cell signalling:IP3 receptors channel calcium into cell death.Curr Biol,2004.14(21):p.R933-5.
65.Orrenius,S.,B.Zhivotovsky,and P.Nicotera,Regulation of cell death:the calcium-apoptosis link.Nat Rev Mol Cell Biol,2003.4(7):p.552-65.
66.Yang,J.,et al.,Identification of a family of calcium sensors as protein ligands of inositol trisphosphate receptor Ca(2+) release channels.Proc Natl Acad Sci USA,2002.99(11):p.7711-6.
67.Berridge,M.J.,P.Lipp,and M.D.Bootman,The versatility and universality of calcium signalling.Nat Rev Mol Cell Biol,2000.1(1):p.11-21.
68.Schneider,T.,et al.,Alpha-1 subunits of voltage gated Ca2+channels in the mesencephalon x neuroblastoma hybrid cell line MES23.5.Neuroscience,1995.68(2):p.479-85.
69.Rusin,K.I.and H.C.Moises,Mu-opioid and GABA(B) receptors modulate different types of Ca2+currents in rat nodose ganglion neurons.Neuroscience,1998.85(3):p.939-56.
70.Robson,K.J.,Sequence diversity in the intron of the calmodulin gene from Plasmodium falciparum.Mol Biochem Parasitol,1993.60(1):p.1-8.
71.Rogers,J.,Calcium-binding proteins:the search for functions.Nature,1989.339(6227):p.661-2.
72.Ankarcrona,M,et al.,Glutamate-induced neuronal death:a succession of necrosis or apoptosis depending on mitochondrial function.Neuron,1995.15(4):p.961-73.
73.Duan,W.,V.M.Rangnekar,and M.P.Mattson,Prostate apoptosis response-4 production in synaptic compartments following apoptotic and excitotoxic insults:evidence for a pivotal role in mitochondrial dysfunction and neuronal degeneration.J Neurochem,1999.72(6):p.2312-22.
74.Dargusch,R.,et al.,The role of Bax in glutamate-induced nerve cell death.J Neurochem,2001.76(1):p.295-301.
75.Culmsee,C.and M.P.Mattson,p53 in neuronal apoptosis.Biochem Biophys Res Commun,2005.331(3):p.761-77.
76.Clague,J.R.and G.A.Langer,The pathogenesis of free radical-induced calcium leak in cultured rat cardiomyocytes.J Mol Cell Cardiol,1994.26(1):p.11-21.
77.Elliott,S.J.,J.G Meszaros,and W.P.Schilling,Effect of oxidant stress on calcium signaling in vascular endothelial cells.Free Radic Biol Med,1992.13(6):p.635-50.
78.Lynch,D.R.and T.M.Dawson,Secondary mechanisms in neuronal trauma.Curr Opin Neurol,1994.7(6):p.510-6.
79.Floyd,R.A.and K.Hensley,Oxidative stress in brain aging.Implications for therapeutics of neurodegenerative diseases.Neurobiol Aging,2002.23(5):p.795-807.
80.Poon,H.F.,et ah,Free radicals:key to brain aging and heme oxygenase as a cellular response to oxidative stress.J Gerontol A Biol Sci Med Sci,2004.59(5):p.478-93.
81.Hyun,D.H.,et ah,The plasma membrane redox system in aging.Ageing Res Rev,2006.5(2):p.209-20.
82.Calabrese,V.,et ah,Mitochondrial involvement in brain function and dysfunction:relevance to aging,neurodegenerative disorders and longevity.Neurochem Res,2001.26(6):p.739-64.
83.Drew,B.and C.Leeuwenburgh,Ageing and subcellular distribution of mitochondria:role of mitochondrial DNA deletions and energy production.Acta Physiol Scand,2004.182(4):p.333-41.
84.Gardian,G.and L.Vecsei,Huntington's disease:pathomechanism and therapeutic perspectives.J Neural Transm,2004.111(10-11):p.1485-94.
85.Mattson,M.P.,Pathways towards and away from Alzheimer's disease.Nature,2004.430(7000):p.631-9.
86.Przedborski,S.and H.Ischiropoulos,Reactive oxygen and nitrogen species:weapons of neuronal destruction in models of Parkinson's disease.Antioxid Redox Signal,2005.7(5-6):p.685-93.
87.Abou-Sleiman,P.M.,M.M.Muqit,and N.W.Wood,Expanding insights of mitochondrial dysfunction in Parkinson's disease.Nat Rev Neurosci,2006.7(3):p.207-19.
88.Mattson,M.P.and A.Cheng,Neurohormetic phytochemicals:Low-dose toxins that induce adaptive neuronal stress responses.Trends Neurosci,2006.29(11):p.632-9.
89.Chan,S.L.,K.Furukawa,and M.P.Mattson,Presenilins and APP in neuritic and synaptic plasticity:implications for the pathogenesis of Alzheimer's disease.Neuromolecular Med,2002.2(2):p.167-96.
90.Greenamyre,J.T.,et al.,Mitochondrial dysfunction in Parkinson's disease.Biochem Soc Symp,1999.66:p.85-97.
91.Brustovetsky,N.,et al.,Age-dependent changes in the calcium sensitivity of striatal mitochondria in mouse models of Huntington's Disease.J Neurochem,2005.93(6):p.1361-70.
92.Kristian,T.and B.K.Siesjo,Calcium in ischemic cell death.Stroke,1998.29(3):p.705-18.
93.Mahley,R.W.,K.H.Weisgraber,and Y.Huang,Apolipoprotein E4:a causative factor and therapeutic target in neuropathology,including Alzheimer's disease.Proc Natl Acad Sci USA,2006.103(15):p.5644-51.
94.Hartmann,H.,A.Eckert,and W.E.Muller,Apolipoprotein E and cholesterol affect neuronal calcium signalling:the possible relationship to beta-amyloid neurotoxicity.Biochem Biophys Res Commun,1994.200(3):p.1185-92.
95.Tolar,M.,et al.,Truncated apolipoprotein E (ApoE) causes increased intracellular calcium and may mediate ApoE neurotoxicity.J Neurosci,1999.19(16):p.7100-10.
96.Pedersen,W.A.,S.L.Chan,and M.P.Mattson,A mechanism for the neuroprotective effect of apolipoprotein E:isoform-specific modification by the lipid peroxidation product 4-hydroxynonenal.J Neurochem,2000.74(4):p.1426-33.
97.Goedert M,S.M.,A Century of Alzheimer's Disease,science,2006.314(5800):p.777-781.
98.Alzheimer,A.,et al.,An English translation of Alzheimer's 1907 paper,“Ubereine eigenartige Erkankung der Hirnrinde”.Clin Anat,1995.8(6):p.429-31.
99.Liu,L.,et al.,Prevalence of dementia in China.Dement Geriatr Cogn Disord,;2003.15(4):p.226-30.
100.Czech C,T.G,Pradier L,Presenilins and Alzheimer's disease:biological functions and pathogenic mechanisms.Prog Neurobiol,2000.60(4):p.363-384.
101.Kang J,L.H.,Unterbeck A,Salbaum JM,Masters CL,Grzeschik KH,Multhaup G,Beyreuther K,Miiller-Hill B,The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor,nature,1987.325(6106):p.733-736.
102.Goldgaber D,L.M.,McBride OW,Saffiotti U,Gajdusek DC,Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer's disease.Science,1987.235(4791):p.877-880.
103.Hardy J,S.D.,The amyloid hypothesis of Alzheimer's disease:progress and problems on the road to therapeutics.Science,2002.297(5580):p.353-356.
104.PH,S.G-H.,Molecular Genetics of Alzheimer's Disease.Biol Psychiatry,2000.47(3):p.183-199.
105.Postina,R.,et al.,A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model.J Clin Invest,2004.113(10):p.1456-64.
106.Teller,J.K.,et al.,Presence of soluble amyloid beta-peptide precedes amyloid plaque formation in Down's syndrome.Nat Med,1996.2(1):p.93-5.
107.Sherrington R,R.E.,Liang Y,Rogaeva EA,Levesque G,Ikeda M,Chi H,Lin C,Li G,Holman K,Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease.Nature,1995.375(6534):p.754-760.
108.Levy-Lahad E,W.W.,Poorkaj P,Romano DM,Oshima J,Pettingell WH,Yu CE,Jondro PD,Schmidt SD,Wang K,et al.,Candidate gene for the chromosome 1 familial Alzheimer's disease locus Science,1995.269(5226):p.973-977.
109.Laudon,H.,et al.,A nine-transmembrane domain topology for presenilin 1.J Biol Chem,2005.280(42):p.35352-60.
110.Grundke-Iqbal I,I.K.,Quinlan M,Tung YC,Zaidi MS,Wisniewski HM,Microtubule-associated protein tau.A component of Alzheimer paired helical filaments.J Biol Chem.1986 May 5;261(13):6084-9,1986.261(13):p.6084-6089.
111.Grundke-Iqbal I,I.K.,Tung YC,Quinlan M,Wisniewski HM,Binder LI,Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology.Proc Natl Acad Sci USA.Jul;,1986.83(13):p.4913-4917.
112.Goedert M,S.M.,Cairns NJ,Crowther RA,Tau proteins of Alzheimer paired helical filaments:abnormal phosphorylation of all six brain isoforms.Neuron,1992.8(1):p.159-168.
113.Biernat J,G.N.,Drewes G,Mandelkow EM,Mandelkow E,Phosphorylation of Ser262 strongly reduces binding of tau to microtubules:distinction between PHF-like immunoreactivity and microtubule binding.Neuron,1993.11(1):p.153-163.
114.Bramblett GT,GM.,Jakes R,Merrick SE,Trojanowski JQ,Lee VM.,Abnormal tau phosphorylation at Ser396 in Alzheimer's disease recapitulates development and contributes to reduced microtubule binding.Neuron,1993.10(6):p.1089-1099.
115.Goedert M,S.M.,Jakes R,Rutherford D,Crowther RA.,Multiple isoforms of human microtubule-associated protein tau:sequences and localization in neurofibrillary tangles of Alzheimer's disease.Neuron,1989.3(4):p.519-526.
116.Hutton M,L.C.,Rizzu P,Baker M,Froelich S,Houlden H,Pickering-Brown S,Chakraverty S,Isaacs A,Grover A,Hackett J,Adamson J,Lincoln S,Dickson D,Davies P,Petersen RC,Stevens M,de Graaff E,Wauters E,van Baren J,Hillebrand M,Joosse M,Kwon JM,Nowotny P,Che LK,Norton J,Morris JC,Reed LA,Trojanowski J,Basun H,Lannfelt L,Neystat M,Fahn S,Dark F,Tannenberg T,Dodd PR,Hayward N,Kwok JB,Schofield PR,Andreadis A,Snowden J,Craufurd D,Neary D,Owen F,Oostra BA,Hardy J,Goate A,van Swieten J,Mann D,Lynch T,Heutink P.,Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17.Nature,1998.393(6686):p.702-705.
117.Poorkaj P,B.T.,Wijsman E,Nemens E,Garruto RM,Anderson L,Andreadis A,Wiederhplt WC,Raskind M,Schellenberg GD.,Tau is a candidate gene for chromosome 17 frontotemporal dementia.Ann Neurol,1998.43(6):p.815-825.
118.Sergeant,N.,A.Wattez,and A.Delacourte,Neurofibrillary degeneration in progressive supranuclear palsy and corticobasal degeneration:tau pathologies with exclusively "exon 10" isoforms.J Neurochem,1999.72(3):p.1243-9.
119.Corder,E.H.,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):p.921-3.
120.Corder,E.H.,et al.,Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease.Nat Genet,1994.7(2):p.180-4.
121.Trommer,B.L.,et al.,ApoE isoform-specific effects on LTP:blockade by oligomeric amyloid-betal-42.Neurobiol Dis,2005.18(1):p.75-82.
122.Bales,K.R.,et al.,Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition.Nat Genet,1997.17(3):p.263-4.
123.Okano,T.,T.Yoshizawa,and Y.Fukada,Pinopsin is a chicken pineal photoreceptive molecule.Nature,1994.372(6501):p.94-7.
124.DeMattos,R.B.,et al.,ApoE and clusterin cooperatively suppress Abeta levels and deposition:evidence that ApoE regulates extracellular Abeta metabolism in vivo.Neuron,2004.41(2):p.193-202.
125.Dow,D.J.,et al.,Alpha-2 macroglobulin polymorphism and Alzheimer disease risk in the UK.Nat Genet,1999.22(1):p.16-7;author reply 21-2.
126.Rogaeva,E.A.,et al.,An alpha-2-macroglobulin insertion-deletion polymorphism in Alzheimer disease.Nat Genet,1999.22(1):p.19-22.
127.Hussain,I.,et al.,Identification of a novel aspartic protease (Asp 2) as beta-secretase.Mol Cell Neurosci,1999.14(6):p.419-27.
128.Luo,Y,et al.,Mice deficient in BACE1,the Alzheimer's beta-secretase,have normal phenotype and abolished beta-amyloid generation.Nat Neurosci,2001.4(3):p.231-2.
129.Citron,M.,Alzheimer's disease:treatments in discovery and development.Nat Neurosci,2002.5 Suppl:p.1055-7.
130.Michel,T.,et al.,Different sedimentation properties of agonist-and antagonist-labelled platelet alpha 2 adrenergic receptors.Biochem Biophys Res Commun,1981.100(3):p.1131-6.
131.Glenner,GG and C.W.Wong,Alzheimer's disease and Down's syndrome:sharing of a unique cerebrovascular amyloid fibril protein.Biochem Biophys Res Commun,1984.122(3):p.1131-5.
132.Glenner GG,W.C.,Quaranta V,Eanes ED.,The amyloid deposits in Alzheimer's disease:their nature and pathogenesis.Appl Pathol,1984.2(6):p.357-369.
133.Lewis J,D.D.,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):p.1487-1491.
134.Jarrett JT,B.E.,Lansbury PT Jr,The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation:implications for the pathogenesis of Alzheimer's disease.Biochemistry,1993.32(18):p.4693-4697.
135.Geula C,W.C.,Saroff D,Lorenzo A,Yuan M,Yankner BA,Aging renders the brain vulnerable to amyloid beta-protein neurotoxicity.Nat Med,1998.4(7):p.827-831.
136.Moechars D,D.I.,Lorent K,Reverse D,Baekelandt V,Naidu A,Tesseur I,Spittaels K,Haute CV,Checler F,Godaux E,Cordell B,Van Leuven F,Early phenotypic changes in transgenic mice that overexpress different mutants of amyloid precursor protein in brain.J Biol Chem,1999.274(10):p.6483-6492.
137.Ajtai,B.M.and M.Kalman,Reactive glia support and guide axon growth in the rat thalamus during the first postnatal week.A sharply timed transition from permissive to non-permissive stage.Int J Dev Neurosci,2001.19(6):p.589-97.
138.Arriagada,P.V.,et al.,Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease.Neurology,1992.42(3 Pt 1):p.631-9.
139.Naslund J,H.V.,Mohs R,Davis KL,Davies P,Greengard P,Buxbaum JD.,Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline.JAMA,2000.283(12):p.1571-1577.
140.Lue LF,K.Y.,Roher AE,Brachova L,Shen Y,Sue L,Beach T,Kurth JH,Rydel RE,Rogers J.,Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer's disease.Am J Pathol,1999.155(3):p.853-862.
141.Hsiao K,C.P.,Nilsen S,Eckman C,Harigaya Y,Younkin S,Yang F,Cole G,Correlative memory deficits,Abeta elevation,and amyloid plaques in transgenic mice.Science,1996.274(5284):p.99-102.
142.M Citron,D.W.,W Xia,G Carlson,T Diehl,G Levesque,Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid-protein in both transfected cells and transgenic mice.Nature Med,1997.3:p.67-72.
143.Mehta ND,R.L.,Eckman C,Sanders S,Yager D,Perez-Tur J,Younkin S,Duff K,Hardy J,Hutton M.,Increased Abeta42(43) from cell lines expressing presenilin 1 mutations.Ann Neurol,1998.43(2):p.256-258.
144.Beglopoulos V,S.X.,Saura CA,Lemere CA,Kim RD,Shen J Reduced (3-Amyloid production and increased inflammatory responses in presenilin conditional knock-out mice.J Biol Chem 2004.279:p.46907-46914.
145.Oddo S,C.A.,Shepherd JD,Murphy MP,Golde TE,Kayed R,Metherate R,Mattson MP,Akbari Y,LaFerla FM.,Triple-transgenic model of Alzheimer's disease with plaques and tangles:intracellular Abeta and synaptic dysfunction.Neuron,2003.39(3):p.409-421.
146.Khachaturian,Z.S.,Calcium,membranes,aging,and Alzheimer's disease.Introduction and overview.Ann N Y Acad Sci,1989.568:p.1-4.
147.Mattson,M.P.,et al.,Calcium signaling in the ER:its role in neuronal plasticity and neurodegenerative disorders.Trends Neurosci,2000.23(5):p.222-9.
148.Etcheberrigaray,R.,et al.,Calcium responses in fibroblasts from asymptomatic members of Alzheimer's disease families.Neurobiol Dis,1998.5(1):p.37-45.
149.Larson,J.,et al.,Alterations in synaptic transmission and long-term potentiation in hippocampal slices from young and aged PDAPP mice.Brain Res,1999.840(1-2):p.23-35.
150.Guo,Q.,et al.,Increased vulnerability of hippocampal neurons from presenilin-1 mutant knock-in mice to amyloid beta-peptide toxicity:central roles of superoxide production and caspase activation.J Neurochem,1999.72(3):p.1019-29.
151.Yoo,A.S.,et al.,Presenilin-mediated modulation of capacitative calcium entry.Neuron,2000.27(3):p.561-72.
152.Chui,D.H.,et al.,Transgenic mice with Alzheimer presenilin 1 mutations show accelerated neurodegeneration without amyloid plaque formation.Nat Med,1999.5(5):p.560-4.
153.Nelson,R.and D.Eisenberg,Recent atomic models of amyloid fibril structure.Curr Opin Struct Biol,2006.16(2):p.260-5.
154.Mattson,M.P.,et al.,beta-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity.J Neurosci,1992.12(2):p.376-89.
155.Mattson,M.P.,K.J.Tomaselli,and R.E.Rydel,Calcium-destabilizing and neurodegenerative effects of aggregated beta-amyloid peptide are attenuated by basic FGF.Brain Res,1993.621(1):p.35-49.
156.Mattson,M.P.,et al.,Comparison of the effects of elevated intracellular aluminum and calcium levels on neuronal survival and tau immunoreactivity.Brain Res,1993.602(1):p.21-31.
157.Mattson,M.P.,Antigenic changes similar to those seen in neurofibrillary tangles are elicited by glutamate and Ca2+influx in cultured hippocampal neurons.Neuron,1990.4(1):p.105-17.
158.Heber,S.,et al.,Mice with combined gene knock-outs reveal essential and partially redundant functions of amyloid precursor protein family members.J Neurosci,2000.20(21):p.7951-63.
159.von Koch,C.S.,et al.,Generation of APLP2 KO mice and early postnatal lethality in APLP2/APP double KO mice.Neurobiol Aging,1997.18(6):p.661-9.
160.Feng R,W.H.,Wang J,Shrom D,Zeng X,Tsien JZ Forebrain degeneration and ventricle enlargement caused by double knockout of Alzheimer's presenilin-1 and presenilin-2.PNAS,2004.101:p.8162-67.
161.Saura CA,C.S.,Beglopoulos V,Malkani S,Zhang D,Shankaranarayana Rao BS,et al,Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration.Neuron,2004.42:p.23-36.
162.Shen J,K.R.r.,The presenilin hypothesis of Alzheimer's disease:evidence for a loss-of-function pathogenic mechanism.Proc Natl Acad Sci USA,2007.104(2):p.403-409.
163.Levitan D,D.T.,Brousseau D,Lee MK,Thinakaran G,Slunt HH,Sisodia SS,Greenwald I,Assessment of normal and mutant human presenilin function in Caenorhabditis elegans.Proc Natl Acad Sci U S A,1996.93(25):p.14940-14944.
164.Wiley JC,H.M.,Kanning KC,Schecterson LC,Bothwell M.,Familial Alzheimer's disease mutations inhibit gamma-secretase-mediated liberation of beta-amyloid precursor protein carboxy-terminal fragment.J Neurochem,2005.94(5):p.1189-1201.
165.Seidner GA,Y.Y.,Faraday MM,Alvord WG,Fortini ME,Modeling clinically heterogeneous presenilin mutations with transgenic Drosophila.Curr Biol.2006 May 23;,2006.16(10):p.1026-1033.
166.Song W,N.P.,Yuan M,Yang X,Shen J,Yankner BA.,Proteolytic release and nuclear translocation of Notch-1 are induced by presenilin-1 and impaired by pathogenic presenilin-1 mutations.Proc Natl Acad Sci USA,1999 96(12):p.6959-6963.
167.Sato T,D.N.,Qi Y,Kakuda N,Misonou H,Mitsumori R,Maruyama H,Koo EH,Haass C,Takio K,Morishima-Kawashima M,Ishiura S,Ihara Y,Potential link between amyloid beta-protein 42 and C-terminal fragment gamma 49-99 of beta-amyloid precursor protein.J Biol Chem,2003.278(27):p.24294-24301.
168.Zhang L,S.L.,Terracina G,Liu Y,Pramanik B,Parker E.,Biochemical characterization of the gamma-secretase activity that produces beta-amyloid peptides.Biochemistry,2001.40(16):p.5049-5055.
169.Moore CL,D.T.,Selkoe DJ,Wolfe MS.,Toward the characterization and identification of gamma-secretases using transition-state analogue inhibitors.Ann N Y Acad Sci,2000.920:p.197-205.
170.Amtul Z,L.P.,Piper S,Crook R,Baker M,Findlay K,Singleton A,Hogg M,Younkin L,Younkin SG,Hardy J,Hutton M,Boeve BF,Tang-Wai D,Golde TE,A presenilin 1 mutation associated with familial frontotemporal dementia inhibits gamma-secretase cleavage of APP and notch.Neurobiol Dis,2002.9(2):p.269-273.
171.Dermaut B,K.-S.S.,Engelborghs S,Theuns J,Rademakers R,Saerens J,Pickut BA,Peeters K,van den Broeck M,Vennekens K,Claes S,Cruts M,Cras P,Martin JJ,Van Broeckhoven C,De Deyn PP,A novel presenilin 1 mutation associated with Pick's disease but not beta-amyloid plaques.Ann Neurol,2004.55(5):p.617-626.
172.Raux G,GR.,Thomas-Anterion C,Boulliat J,Verpillat P,Hannequin D,Brice A,Frebourg T,Campion D,Dementia with prominent frontotemporal features associated with L113P presenilin 1 mutation.Neurology.2000 Nov 28;,2000.55(10):p.1577-1578.
173.Cuzzocrea,S.,C.Thiemermann,and D.Salvemini,Potential therapeutic effect of antioxidant therapy in shock and inflammation.Curr Med Chem,2004.11(9):p.1147-62.
174.Kovacic,P.and J.D.Jacintho,Mechanisms of carcinogenesis:focus on oxidative stress and electron transfer.Curr Med Chem,2001.8(7):p.773-96.
175.Takano,H.,et al.,Oxidative stress-induced signal transduction pathways in cardiac myocytes:involvement of ROS in heart diseases.Antioxid Redox Signal,2003.5(6):p.789-94.
176.Zhu,X.,et al.,Oxidative stress signalling in Alzheimer's disease.Brain Res,2004.1000(1-2):p.32-9.
177.Emerit,J.,M.Edeas,and F.Bricaire,Neurodegenerative diseases and oxidative stress.Biomed Pharmacother,2004.58(1):p.39-46.
178.Perry,G,et al.,Oxidative damage in Alzheimer's disease:the metabolic dimension.Int J Dev Neurosci,2000.18(4-5):p.417-21.
179.Cottrell,D.A.,et al.,Mitochondrial enzyme-deficient hippocampal neurons and choroidal cells in AD.Neurology,2001.57(2):p.260-4.
180.Takashima,A.,et al.,Activation of tau protein kinase I/glycogen synthase kinase-3beta by amyloid beta peptide (25-35) enhances phosphorylation of tau in hippocampal neurons.Neurosci Res,1998.31(4):p.317-23.
181.Auld,D.S.,et al.,Alzheimer's disease and the basal forebrain cholinergic system:relations to beta-amyloid peptides,cognition,and treatment strategies.Prog Neurobiol,2002.68(3):p.209-45.
182.Brenner,D.E.,et al.,Relationship between cigarette smoking and Alzheimer's disease in a population-based case-control study.Neurology,1993.43(2):p.293-300.
183.Svensson,A.L.and A.Nordberg,Beta-estradiol attenuate amyloid beta-peptide toxicity via nicotinic receptors.Neuroreport,1999.10(17):p.3485-9.
2.Chan,S.L.and M.R Mattson,Caspase and calpain substrates:roles in synaptic plasticity and cell death.J Neurosci Res,1999.58(1):p.167-90.
3.Nixon,R.A.,The calpains in aging and aging-related diseases.Ageing Res Rev,2003.2(4):p.407-18.
4.Leist,M.,et al.,Peroxynitrite and nitric oxide donors induce neuronal apoptosis by eliciting autocrine excitotoxicity.Eur J Neurosci,1997.9(7):p.1488-98.
5.Stefanis,L.,Caspase-dependent and-independent neuronal death:two distinct pathways to neuronal injury.Neuroscientist,2005.11(1):p.50-62.
6.Lafon-Cazal,M.,et al.,NMDA-dependent superoxide production and neurotoxicity.Nature,1993.364(6437):p.535-7.
7.Mattson,M.P.and M.Sherman,Perturbed signal transduction in neurodegenerative disorders involving aberrant protein aggregation.Neuromolecular Med,2003.4(1-2):p.109-32.
8.Gibson,G.E.,Interactions of oxidative stress with cellular calcium dynamics and glucose metabolism in Alzheimer's disease.Free Radic Biol Med,2002.32(11):p.1061-70.
9.Qin,S.,E.R.Stadtman,and P.B.Chock,Regulation of oxidative stress-induced calcium release by phosphatidylinositol 3-kinase and Bruton's tyrosine kinase in B cells.Proc Natl Acad Sci USA,2000.97(13):p.7118-23.
10.Zhao,Z.,et al.,One-step solid-phase extraction procedure for F(2)-isoprostanes.Clin Chem,2001.47(7):p.1306-8.
11.Berridge,M.J.,M.D.Bootman,and P.Lipp,Calcium--a life and death signal.Nature,1998.395(6703):p.645-8.
12.Marin,J.,et al.,Mechanisms involved in the cellular calcium homeostasis in vascular smooth muscle:calcium pumps.Life Sci,1999.64(5):p.279-303.
13.Halliwell,B.,Oxygen radicals as key mediators in neurological disease:fact or fiction? Ann Neurol,1992.32 Suppl:p.S10-5.
14.Suh,Y.H.and F.Checler,Amyloid precursor protein,presenilins,and alpha-synuclein:molecular pathogenesis and pharmacological applications in Alzheimer's disease.Pharmacol Rev,2002.54(3):p.469-525.
15.Hardy,J.A.and GA.Higgins,Alzheimer's disease:the amyloid cascade hypothesis.Science,1992.256(5054):p.184-5.
16.Hardy,J.and D.J.Selkoe,The amyloid hypothesis of Alzheimer's disease:progress and problems on the road to therapeutics.Science,2002.297(5580):p.353-6.
17.Stutzmann,G.E.,et al.,Enhanced ryanodine receptor recruitment contributes to Ca2+disruptions in young,adult,and aged Alzheimer's disease mice.J Neurosci,2006.26(19):p.5180-9.
18.Fortini,M.E.,Neurobiology:double trouble for neurons.Nature,2003.425(6958):p.565-6.
19.Wilquet,V.and B.De Strooper,Amyloid-beta precursor protein processing in neurodegeneration.Curr Opin Neurobiol,2004.14(5):p.582-8.
20.Campion,D.,et al.,Mutations of the presenilin I gene in families with early-onset Alzheimer's disease.Hum Mol Genet,1995.4(12):p.2373-7.
21.Shen,J.,et al.,Skeletal and CNS defects in Presenilin-1-deficient mice.Cell,1997.89(4):p.629-39.
22.Wong,P.C.,et al.,Presenilin 1 is required for Notchl and Dill expression in the paraxial mesoderm.Nature,1997.387(6630):p.288-92.
23.Feng,R.,et al.,Forebrain degeneration and ventricle enlargement caused by double knockout of Alzheimer's presenilin-1 and presenilin-2.Proc Natl Acad Sci USA,2004.101(21):p.8162-7.
24.Pratico,D.,et al.,Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer amyloidosis.J Neurosci,2001.21(12):p.4183-7.
25.Donoviel,D.B.,et al.,Mice lacking both presenilin genes exhibit early embryonic patterning defects.Genes Dev,1999.13(21):p.2801-10.
26.Steiner,H.,et al.,A loss of function mutation of presenilin-2 interferes with amyloid beta-peptide production and notch signaling.J Biol Chem,1999.274(40):p.28669-73.
27.Lai,M.T.,et al.,Presenilin-1 and presenilin-2 exhibit distinct yet overlapping gamma-secretase activities.J Biol Chem,2003.278(25):p.22475-81.
28.Montine,T.J.,et al.,Lipid peroxidation in aging brain and Alzheimer's disease.Free Radic Biol Med,2002.33(5):p.620-6.
29.Tamagno,E.,et al.,Oxidative stress activates a positive feedback between the gamma-and beta-secretase cleavages of the beta-amyloid precursor protein.J Neurochem,2008.104(3):p.683-95.
30.Hwang,E.S.and G.H.Kim,Biomarkers for oxidative stress status of DNA,lipids,and proteins in vitro and in vivo cancer research.Toxicology,2007.229(1-2):p.1-10.
31.Tamagno,E.,et al.,The various aggregation states of beta-amyloid 1-42 mediate different effects on oxidative stress,neurodegeneration,and BACE-1 expression.Free Radic Biol Med,2006.41(2):p.202-12.
32.Beal,M.F.,Oxidative damage as an early marker of Alzheimer's disease and mild cognitive impairment.Neurobiol Aging,2005.26(5):p.585-6.
33.Keller,J.N.,et al.,Evidence of increased oxidative damage in subjects with mild cognitive impairment.Neurology,2005.64(7):p.1152-6.
34.Lovell,M.A.and W.R.Markesbery,Oxidative damage in mild cognitive impairment and early Alzheimer's disease.J Neurosci Res,2007.85(14):p.3036-40.
35.Arlt,S.,U.Beisiegel,and A.KontUsh,Lipid peroxidation in neurodegeneration:new insights into Alzheimer's disease.Curr Opin Lipidol,2002.13(3):p.289-94.
36.Butterfield,D.A.,M.Perluigi,and R.Sultana,Oxidative stress in Alzheimer's disease brain:new insights from redox proteomics.Eur J Pharmacol,2006.545(1):p.39-50.
37.Volkel,W.,et al.,Increased brain levels of 4-hydroxy-2-nonenal glutathione conjugates in severe Alzheimer's disease.Neurochem Int,2006.48(8):p.679-86.
38.Wang,J.,W.R.Markesbery,and M.A.Lovell,Increased oxidative damage in nuclear and mitochondrial DNA in mild cognitive impairment.J Neurochem,2006.96(3):p.825-32.
39.Cecchi,C,et al.,Oxidative stress and reduced antioxidant defenses in peripheral cells from familial Alzheimer's patients.Free Radic Biol Med,2002.33(10):p.1372-9.
40.Migliore,L.,et al.,Oxidative DNA damage in peripheral leukocytes of mild cognitive impairment and AD patients.Neurobiol Aging,2005.26(5):p.567-73.
41.Chauhan,V.and A.Chauhan,Oxidative stress in Alzheimer's disease.Pathophysiology,2006.13(3):p.195-208.
42.Tu,H.,et al.,Presenilins form ER Ca2+leak channels,a function disrupted by familial Alzheimer's disease-linked mutations.Cell,2006.126(5):p.981-93.
43.Musiek,E.S.,et al.,Quantification of F-ring isoprostane-like compounds (F4-neuroprostanes) derived from docosahexaenoic acid in vivo in humans by a stable isotope dilution mass spectrometric assay.J Chromatogr B Analyt Technol Biomed Life Sci,2004.799(1):p.95-102.
44.De Strooper,B.,Loss-of-function presenilin mutations in Alzheimer disease.Talking Point on the role of presenilin mutations in Alzheimer disease.EMBO Rep,2007.8(2):p.141-6.
45.Saura,C.A.,et al.,Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration.Neuron,2004.42(1):p.23-36.
46.Turner,R.S.,Alzheimer's Disease in Man and Transgenic Mice :Females at Higher Risk.Am J Pathol,2001.158(3):p.797-801.
47.Yao,J.,et al.,Aging,gender and APOE isotype modulate metabolism of Alzheimer's Abeta peptides and F-isoprostanes in the absence of detectable amyloid deposits.J Neurochem,2004.90(4):p.1011-8.
48.Vina,J.,et al.,Effect of gender on mitochondrial toxicity of Alzheimer's Abeta peptide.Antioxid Redox Signal,2007.9(10):p.1677-90.
49.Candore,G,et al.,Age-related inflammatory diseases:role of genetics and gender in the pathophysiology of Alzheimer's disease.Ann N Y Acad Sci,2006.1089:p.472-86.
50.Guo,Q.,et al.,Alzheimer's PS-1 mutation perturbs calcium homeostasis and sensitizes PC 12 cells to death induced by amyloid beta-peptide.Neuroreport,1996.8(1):p.379-83.
51.Leissring,M.A.,et al.,Capacitative calcium entry deficits and elevated luminal calcium content in mutant presenilin-1 knockin mice.J Cell Biol, 2000.149(4):p.793-8.
52.Leissring,M.A.,et al.,Alzheimer's presenilin-1 mutation potentiates inositol 1,4,5-trisphosphate-mediated calcium signaling in Xenopus oocytes.J Neurochem,1999.72(3):p.1061-8.
53.Leissring,M.A.,I.Parker,and F.M.LaFerla,Presenilin-2 mutations modulate amplitude and kinetics of inositol 1,4,5-trisphosphate-mediated calcium signals.J Biol Chem,1999.274(46):p.32535-8.
54.Leissring,M.A.,et al.,A physiologic signaling role for the gamma-secretase-derived intracellular fragment of APR Proc Natl Acad Sci USA,2002.99(7):p.4697-702.
55.Nelson,O.,et al.,Familial Alzheimer disease-linked mutations specifically disrupt Ca2+leak function of presenilin 1.J Clin Invest,2007.117(5):p.1230-9.
56.Yang,Y.and D.G Cook,Presenilin-1 deficiency impairs glutamate-evoked intracellular calcium responses in neurons.Neuroscience,2004.124(3):p.501-5.
57.Zatti,G,et al.,Presenilin mutations linked to familial Alzheimer's disease reduce endoplasmic reticulum and Golgi apparatus calcium levels.Cell Calcium,2006.39(6):p.539-50.
58.Herms,J.,et al.,Capacitive calcium entry is directly attenuated by mutant presenilin-1,independent of the expression of the amyloid precursor protein.J Biol Chem,2003.278(4):p.2484-9.
59.Xie,L.H.,et al.,Oxidative-stress-induced afterdepolarizations and calmodulin kinase Ⅱ signaling.Circ Res,2009.104(1):p.79-86.
60.Griffith,L.C.,CaMKⅡ:new tricks for an old dog.Cell,2008.133(3):p.397-9.
61.Malenka,R.C.,et al.,An essential role for postsynaptic calmodulin and protein kinase activity in long-term potentiation.Nature,1989.340(6234):p.554-7.
62.Miller,P.,et al.,The stability of a stochastic CaMKⅡ switch:dependence on the number of enzyme molecules and protein turnover.PLoS Biol,2005.3(4):p.el07.
63.Liwen Sun,L.W.,Yong Sun,Syao-wei Tang and Yinghe Hu,Protective effects of EUK4010 on b-amyloid(l-42) induced degeneration of neuronal cells.European Journal of Neuroscience,2006.24:p.1011-1019.
64.Hanson,C.J.,M.D.Bootman,and H.L.Roderick,Cell signalling:IP3 receptors channel calcium into cell death.Curr Biol,2004.14(21):p.R933-5.
65.Orrenius,S.,B.Zhivotovsky,and P.Nicotera,Regulation of cell death:the calcium-apoptosis link.Nat Rev Mol Cell Biol,2003.4(7):p.552-65.
66.Yang,J.,et al.,Identification of a family of calcium sensors as protein ligands of inositol trisphosphate receptor Ca(2+) release channels.Proc Natl Acad Sci USA,2002.99(11):p.7711-6.
67.Berridge,M.J.,P.Lipp,and M.D.Bootman,The versatility and universality of calcium signalling.Nat Rev Mol Cell Biol,2000.1(1):p.11-21.
68.Schneider,T.,et al.,Alpha-1 subunits of voltage gated Ca2+channels in the mesencephalon x neuroblastoma hybrid cell line MES23.5.Neuroscience,1995.68(2):p.479-85.
69.Rusin,K.I.and H.C.Moises,Mu-opioid and GABA(B) receptors modulate different types of Ca2+currents in rat nodose ganglion neurons.Neuroscience,1998.85(3):p.939-56.
70.Robson,K.J.,Sequence diversity in the intron of the calmodulin gene from Plasmodium falciparum.Mol Biochem Parasitol,1993.60(1):p.1-8.
71.Rogers,J.,Calcium-binding proteins:the search for functions.Nature,1989.339(6227):p.661-2.
72.Ankarcrona,M,et al.,Glutamate-induced neuronal death:a succession of necrosis or apoptosis depending on mitochondrial function.Neuron,1995.15(4):p.961-73.
73.Duan,W.,V.M.Rangnekar,and M.P.Mattson,Prostate apoptosis response-4 production in synaptic compartments following apoptotic and excitotoxic insults:evidence for a pivotal role in mitochondrial dysfunction and neuronal degeneration.J Neurochem,1999.72(6):p.2312-22.
74.Dargusch,R.,et al.,The role of Bax in glutamate-induced nerve cell death.J Neurochem,2001.76(1):p.295-301.
75.Culmsee,C.and M.P.Mattson,p53 in neuronal apoptosis.Biochem Biophys Res Commun,2005.331(3):p.761-77.
76.Clague,J.R.and G.A.Langer,The pathogenesis of free radical-induced calcium leak in cultured rat cardiomyocytes.J Mol Cell Cardiol,1994.26(1):p.11-21.
77.Elliott,S.J.,J.G Meszaros,and W.P.Schilling,Effect of oxidant stress on calcium signaling in vascular endothelial cells.Free Radic Biol Med,1992.13(6):p.635-50.
78.Lynch,D.R.and T.M.Dawson,Secondary mechanisms in neuronal trauma.Curr Opin Neurol,1994.7(6):p.510-6.
79.Floyd,R.A.and K.Hensley,Oxidative stress in brain aging.Implications for therapeutics of neurodegenerative diseases.Neurobiol Aging,2002.23(5):p.795-807.
80.Poon,H.F.,et ah,Free radicals:key to brain aging and heme oxygenase as a cellular response to oxidative stress.J Gerontol A Biol Sci Med Sci,2004.59(5):p.478-93.
81.Hyun,D.H.,et ah,The plasma membrane redox system in aging.Ageing Res Rev,2006.5(2):p.209-20.
82.Calabrese,V.,et ah,Mitochondrial involvement in brain function and dysfunction:relevance to aging,neurodegenerative disorders and longevity.Neurochem Res,2001.26(6):p.739-64.
83.Drew,B.and C.Leeuwenburgh,Ageing and subcellular distribution of mitochondria:role of mitochondrial DNA deletions and energy production.Acta Physiol Scand,2004.182(4):p.333-41.
84.Gardian,G.and L.Vecsei,Huntington's disease:pathomechanism and therapeutic perspectives.J Neural Transm,2004.111(10-11):p.1485-94.
85.Mattson,M.P.,Pathways towards and away from Alzheimer's disease.Nature,2004.430(7000):p.631-9.
86.Przedborski,S.and H.Ischiropoulos,Reactive oxygen and nitrogen species:weapons of neuronal destruction in models of Parkinson's disease.Antioxid Redox Signal,2005.7(5-6):p.685-93.
87.Abou-Sleiman,P.M.,M.M.Muqit,and N.W.Wood,Expanding insights of mitochondrial dysfunction in Parkinson's disease.Nat Rev Neurosci,2006.7(3):p.207-19.
88.Mattson,M.P.and A.Cheng,Neurohormetic phytochemicals:Low-dose toxins that induce adaptive neuronal stress responses.Trends Neurosci,2006.29(11):p.632-9.
89.Chan,S.L.,K.Furukawa,and M.P.Mattson,Presenilins and APP in neuritic and synaptic plasticity:implications for the pathogenesis of Alzheimer's disease.Neuromolecular Med,2002.2(2):p.167-96.
90.Greenamyre,J.T.,et al.,Mitochondrial dysfunction in Parkinson's disease.Biochem Soc Symp,1999.66:p.85-97.
91.Brustovetsky,N.,et al.,Age-dependent changes in the calcium sensitivity of striatal mitochondria in mouse models of Huntington's Disease.J Neurochem,2005.93(6):p.1361-70.
92.Kristian,T.and B.K.Siesjo,Calcium in ischemic cell death.Stroke,1998.29(3):p.705-18.
93.Mahley,R.W.,K.H.Weisgraber,and Y.Huang,Apolipoprotein E4:a causative factor and therapeutic target in neuropathology,including Alzheimer's disease.Proc Natl Acad Sci USA,2006.103(15):p.5644-51.
94.Hartmann,H.,A.Eckert,and W.E.Muller,Apolipoprotein E and cholesterol affect neuronal calcium signalling:the possible relationship to beta-amyloid neurotoxicity.Biochem Biophys Res Commun,1994.200(3):p.1185-92.
95.Tolar,M.,et al.,Truncated apolipoprotein E (ApoE) causes increased intracellular calcium and may mediate ApoE neurotoxicity.J Neurosci,1999.19(16):p.7100-10.
96.Pedersen,W.A.,S.L.Chan,and M.P.Mattson,A mechanism for the neuroprotective effect of apolipoprotein E:isoform-specific modification by the lipid peroxidation product 4-hydroxynonenal.J Neurochem,2000.74(4):p.1426-33.
97.Goedert M,S.M.,A Century of Alzheimer's Disease,science,2006.314(5800):p.777-781.
98.Alzheimer,A.,et al.,An English translation of Alzheimer's 1907 paper,“Ubereine eigenartige Erkankung der Hirnrinde”.Clin Anat,1995.8(6):p.429-31.
99.Liu,L.,et al.,Prevalence of dementia in China.Dement Geriatr Cogn Disord,;2003.15(4):p.226-30.
100.Czech C,T.G,Pradier L,Presenilins and Alzheimer's disease:biological functions and pathogenic mechanisms.Prog Neurobiol,2000.60(4):p.363-384.
101.Kang J,L.H.,Unterbeck A,Salbaum JM,Masters CL,Grzeschik KH,Multhaup G,Beyreuther K,Miiller-Hill B,The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor,nature,1987.325(6106):p.733-736.
102.Goldgaber D,L.M.,McBride OW,Saffiotti U,Gajdusek DC,Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer's disease.Science,1987.235(4791):p.877-880.
103.Hardy J,S.D.,The amyloid hypothesis of Alzheimer's disease:progress and problems on the road to therapeutics.Science,2002.297(5580):p.353-356.
104.PH,S.G-H.,Molecular Genetics of Alzheimer's Disease.Biol Psychiatry,2000.47(3):p.183-199.
105.Postina,R.,et al.,A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model.J Clin Invest,2004.113(10):p.1456-64.
106.Teller,J.K.,et al.,Presence of soluble amyloid beta-peptide precedes amyloid plaque formation in Down's syndrome.Nat Med,1996.2(1):p.93-5.
107.Sherrington R,R.E.,Liang Y,Rogaeva EA,Levesque G,Ikeda M,Chi H,Lin C,Li G,Holman K,Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease.Nature,1995.375(6534):p.754-760.
108.Levy-Lahad E,W.W.,Poorkaj P,Romano DM,Oshima J,Pettingell WH,Yu CE,Jondro PD,Schmidt SD,Wang K,et al.,Candidate gene for the chromosome 1 familial Alzheimer's disease locus Science,1995.269(5226):p.973-977.
109.Laudon,H.,et al.,A nine-transmembrane domain topology for presenilin 1.J Biol Chem,2005.280(42):p.35352-60.
110.Grundke-Iqbal I,I.K.,Quinlan M,Tung YC,Zaidi MS,Wisniewski HM,Microtubule-associated protein tau.A component of Alzheimer paired helical filaments.J Biol Chem.1986 May 5;261(13):6084-9,1986.261(13):p.6084-6089.
111.Grundke-Iqbal I,I.K.,Tung YC,Quinlan M,Wisniewski HM,Binder LI,Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology.Proc Natl Acad Sci USA.Jul;,1986.83(13):p.4913-4917.
112.Goedert M,S.M.,Cairns NJ,Crowther RA,Tau proteins of Alzheimer paired helical filaments:abnormal phosphorylation of all six brain isoforms.Neuron,1992.8(1):p.159-168.
113.Biernat J,G.N.,Drewes G,Mandelkow EM,Mandelkow E,Phosphorylation of Ser262 strongly reduces binding of tau to microtubules:distinction between PHF-like immunoreactivity and microtubule binding.Neuron,1993.11(1):p.153-163.
114.Bramblett GT,GM.,Jakes R,Merrick SE,Trojanowski JQ,Lee VM.,Abnormal tau phosphorylation at Ser396 in Alzheimer's disease recapitulates development and contributes to reduced microtubule binding.Neuron,1993.10(6):p.1089-1099.
115.Goedert M,S.M.,Jakes R,Rutherford D,Crowther RA.,Multiple isoforms of human microtubule-associated protein tau:sequences and localization in neurofibrillary tangles of Alzheimer's disease.Neuron,1989.3(4):p.519-526.
116.Hutton M,L.C.,Rizzu P,Baker M,Froelich S,Houlden H,Pickering-Brown S,Chakraverty S,Isaacs A,Grover A,Hackett J,Adamson J,Lincoln S,Dickson D,Davies P,Petersen RC,Stevens M,de Graaff E,Wauters E,van Baren J,Hillebrand M,Joosse M,Kwon JM,Nowotny P,Che LK,Norton J,Morris JC,Reed LA,Trojanowski J,Basun H,Lannfelt L,Neystat M,Fahn S,Dark F,Tannenberg T,Dodd PR,Hayward N,Kwok JB,Schofield PR,Andreadis A,Snowden J,Craufurd D,Neary D,Owen F,Oostra BA,Hardy J,Goate A,van Swieten J,Mann D,Lynch T,Heutink P.,Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17.Nature,1998.393(6686):p.702-705.
117.Poorkaj P,B.T.,Wijsman E,Nemens E,Garruto RM,Anderson L,Andreadis A,Wiederhplt WC,Raskind M,Schellenberg GD.,Tau is a candidate gene for chromosome 17 frontotemporal dementia.Ann Neurol,1998.43(6):p.815-825.
118.Sergeant,N.,A.Wattez,and A.Delacourte,Neurofibrillary degeneration in progressive supranuclear palsy and corticobasal degeneration:tau pathologies with exclusively "exon 10" isoforms.J Neurochem,1999.72(3):p.1243-9.
119.Corder,E.H.,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):p.921-3.
120.Corder,E.H.,et al.,Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease.Nat Genet,1994.7(2):p.180-4.
121.Trommer,B.L.,et al.,ApoE isoform-specific effects on LTP:blockade by oligomeric amyloid-betal-42.Neurobiol Dis,2005.18(1):p.75-82.
122.Bales,K.R.,et al.,Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition.Nat Genet,1997.17(3):p.263-4.
123.Okano,T.,T.Yoshizawa,and Y.Fukada,Pinopsin is a chicken pineal photoreceptive molecule.Nature,1994.372(6501):p.94-7.
124.DeMattos,R.B.,et al.,ApoE and clusterin cooperatively suppress Abeta levels and deposition:evidence that ApoE regulates extracellular Abeta metabolism in vivo.Neuron,2004.41(2):p.193-202.
125.Dow,D.J.,et al.,Alpha-2 macroglobulin polymorphism and Alzheimer disease risk in the UK.Nat Genet,1999.22(1):p.16-7;author reply 21-2.
126.Rogaeva,E.A.,et al.,An alpha-2-macroglobulin insertion-deletion polymorphism in Alzheimer disease.Nat Genet,1999.22(1):p.19-22.
127.Hussain,I.,et al.,Identification of a novel aspartic protease (Asp 2) as beta-secretase.Mol Cell Neurosci,1999.14(6):p.419-27.
128.Luo,Y,et al.,Mice deficient in BACE1,the Alzheimer's beta-secretase,have normal phenotype and abolished beta-amyloid generation.Nat Neurosci,2001.4(3):p.231-2.
129.Citron,M.,Alzheimer's disease:treatments in discovery and development.Nat Neurosci,2002.5 Suppl:p.1055-7.
130.Michel,T.,et al.,Different sedimentation properties of agonist-and antagonist-labelled platelet alpha 2 adrenergic receptors.Biochem Biophys Res Commun,1981.100(3):p.1131-6.
131.Glenner,GG and C.W.Wong,Alzheimer's disease and Down's syndrome:sharing of a unique cerebrovascular amyloid fibril protein.Biochem Biophys Res Commun,1984.122(3):p.1131-5.
132.Glenner GG,W.C.,Quaranta V,Eanes ED.,The amyloid deposits in Alzheimer's disease:their nature and pathogenesis.Appl Pathol,1984.2(6):p.357-369.
133.Lewis J,D.D.,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):p.1487-1491.
134.Jarrett JT,B.E.,Lansbury PT Jr,The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation:implications for the pathogenesis of Alzheimer's disease.Biochemistry,1993.32(18):p.4693-4697.
135.Geula C,W.C.,Saroff D,Lorenzo A,Yuan M,Yankner BA,Aging renders the brain vulnerable to amyloid beta-protein neurotoxicity.Nat Med,1998.4(7):p.827-831.
136.Moechars D,D.I.,Lorent K,Reverse D,Baekelandt V,Naidu A,Tesseur I,Spittaels K,Haute CV,Checler F,Godaux E,Cordell B,Van Leuven F,Early phenotypic changes in transgenic mice that overexpress different mutants of amyloid precursor protein in brain.J Biol Chem,1999.274(10):p.6483-6492.
137.Ajtai,B.M.and M.Kalman,Reactive glia support and guide axon growth in the rat thalamus during the first postnatal week.A sharply timed transition from permissive to non-permissive stage.Int J Dev Neurosci,2001.19(6):p.589-97.
138.Arriagada,P.V.,et al.,Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease.Neurology,1992.42(3 Pt 1):p.631-9.
139.Naslund J,H.V.,Mohs R,Davis KL,Davies P,Greengard P,Buxbaum JD.,Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline.JAMA,2000.283(12):p.1571-1577.
140.Lue LF,K.Y.,Roher AE,Brachova L,Shen Y,Sue L,Beach T,Kurth JH,Rydel RE,Rogers J.,Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer's disease.Am J Pathol,1999.155(3):p.853-862.
141.Hsiao K,C.P.,Nilsen S,Eckman C,Harigaya Y,Younkin S,Yang F,Cole G,Correlative memory deficits,Abeta elevation,and amyloid plaques in transgenic mice.Science,1996.274(5284):p.99-102.
142.M Citron,D.W.,W Xia,G Carlson,T Diehl,G Levesque,Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid-protein in both transfected cells and transgenic mice.Nature Med,1997.3:p.67-72.
143.Mehta ND,R.L.,Eckman C,Sanders S,Yager D,Perez-Tur J,Younkin S,Duff K,Hardy J,Hutton M.,Increased Abeta42(43) from cell lines expressing presenilin 1 mutations.Ann Neurol,1998.43(2):p.256-258.
144.Beglopoulos V,S.X.,Saura CA,Lemere CA,Kim RD,Shen J Reduced (3-Amyloid production and increased inflammatory responses in presenilin conditional knock-out mice.J Biol Chem 2004.279:p.46907-46914.
145.Oddo S,C.A.,Shepherd JD,Murphy MP,Golde TE,Kayed R,Metherate R,Mattson MP,Akbari Y,LaFerla FM.,Triple-transgenic model of Alzheimer's disease with plaques and tangles:intracellular Abeta and synaptic dysfunction.Neuron,2003.39(3):p.409-421.
146.Khachaturian,Z.S.,Calcium,membranes,aging,and Alzheimer's disease.Introduction and overview.Ann N Y Acad Sci,1989.568:p.1-4.
147.Mattson,M.P.,et al.,Calcium signaling in the ER:its role in neuronal plasticity and neurodegenerative disorders.Trends Neurosci,2000.23(5):p.222-9.
148.Etcheberrigaray,R.,et al.,Calcium responses in fibroblasts from asymptomatic members of Alzheimer's disease families.Neurobiol Dis,1998.5(1):p.37-45.
149.Larson,J.,et al.,Alterations in synaptic transmission and long-term potentiation in hippocampal slices from young and aged PDAPP mice.Brain Res,1999.840(1-2):p.23-35.
150.Guo,Q.,et al.,Increased vulnerability of hippocampal neurons from presenilin-1 mutant knock-in mice to amyloid beta-peptide toxicity:central roles of superoxide production and caspase activation.J Neurochem,1999.72(3):p.1019-29.
151.Yoo,A.S.,et al.,Presenilin-mediated modulation of capacitative calcium entry.Neuron,2000.27(3):p.561-72.
152.Chui,D.H.,et al.,Transgenic mice with Alzheimer presenilin 1 mutations show accelerated neurodegeneration without amyloid plaque formation.Nat Med,1999.5(5):p.560-4.
153.Nelson,R.and D.Eisenberg,Recent atomic models of amyloid fibril structure.Curr Opin Struct Biol,2006.16(2):p.260-5.
154.Mattson,M.P.,et al.,beta-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity.J Neurosci,1992.12(2):p.376-89.
155.Mattson,M.P.,K.J.Tomaselli,and R.E.Rydel,Calcium-destabilizing and neurodegenerative effects of aggregated beta-amyloid peptide are attenuated by basic FGF.Brain Res,1993.621(1):p.35-49.
156.Mattson,M.P.,et al.,Comparison of the effects of elevated intracellular aluminum and calcium levels on neuronal survival and tau immunoreactivity.Brain Res,1993.602(1):p.21-31.
157.Mattson,M.P.,Antigenic changes similar to those seen in neurofibrillary tangles are elicited by glutamate and Ca2+influx in cultured hippocampal neurons.Neuron,1990.4(1):p.105-17.
158.Heber,S.,et al.,Mice with combined gene knock-outs reveal essential and partially redundant functions of amyloid precursor protein family members.J Neurosci,2000.20(21):p.7951-63.
159.von Koch,C.S.,et al.,Generation of APLP2 KO mice and early postnatal lethality in APLP2/APP double KO mice.Neurobiol Aging,1997.18(6):p.661-9.
160.Feng R,W.H.,Wang J,Shrom D,Zeng X,Tsien JZ Forebrain degeneration and ventricle enlargement caused by double knockout of Alzheimer's presenilin-1 and presenilin-2.PNAS,2004.101:p.8162-67.
161.Saura CA,C.S.,Beglopoulos V,Malkani S,Zhang D,Shankaranarayana Rao BS,et al,Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration.Neuron,2004.42:p.23-36.
162.Shen J,K.R.r.,The presenilin hypothesis of Alzheimer's disease:evidence for a loss-of-function pathogenic mechanism.Proc Natl Acad Sci USA,2007.104(2):p.403-409.
163.Levitan D,D.T.,Brousseau D,Lee MK,Thinakaran G,Slunt HH,Sisodia SS,Greenwald I,Assessment of normal and mutant human presenilin function in Caenorhabditis elegans.Proc Natl Acad Sci U S A,1996.93(25):p.14940-14944.
164.Wiley JC,H.M.,Kanning KC,Schecterson LC,Bothwell M.,Familial Alzheimer's disease mutations inhibit gamma-secretase-mediated liberation of beta-amyloid precursor protein carboxy-terminal fragment.J Neurochem,2005.94(5):p.1189-1201.
165.Seidner GA,Y.Y.,Faraday MM,Alvord WG,Fortini ME,Modeling clinically heterogeneous presenilin mutations with transgenic Drosophila.Curr Biol.2006 May 23;,2006.16(10):p.1026-1033.
166.Song W,N.P.,Yuan M,Yang X,Shen J,Yankner BA.,Proteolytic release and nuclear translocation of Notch-1 are induced by presenilin-1 and impaired by pathogenic presenilin-1 mutations.Proc Natl Acad Sci USA,1999 96(12):p.6959-6963.
167.Sato T,D.N.,Qi Y,Kakuda N,Misonou H,Mitsumori R,Maruyama H,Koo EH,Haass C,Takio K,Morishima-Kawashima M,Ishiura S,Ihara Y,Potential link between amyloid beta-protein 42 and C-terminal fragment gamma 49-99 of beta-amyloid precursor protein.J Biol Chem,2003.278(27):p.24294-24301.
168.Zhang L,S.L.,Terracina G,Liu Y,Pramanik B,Parker E.,Biochemical characterization of the gamma-secretase activity that produces beta-amyloid peptides.Biochemistry,2001.40(16):p.5049-5055.
169.Moore CL,D.T.,Selkoe DJ,Wolfe MS.,Toward the characterization and identification of gamma-secretases using transition-state analogue inhibitors.Ann N Y Acad Sci,2000.920:p.197-205.
170.Amtul Z,L.P.,Piper S,Crook R,Baker M,Findlay K,Singleton A,Hogg M,Younkin L,Younkin SG,Hardy J,Hutton M,Boeve BF,Tang-Wai D,Golde TE,A presenilin 1 mutation associated with familial frontotemporal dementia inhibits gamma-secretase cleavage of APP and notch.Neurobiol Dis,2002.9(2):p.269-273.
171.Dermaut B,K.-S.S.,Engelborghs S,Theuns J,Rademakers R,Saerens J,Pickut BA,Peeters K,van den Broeck M,Vennekens K,Claes S,Cruts M,Cras P,Martin JJ,Van Broeckhoven C,De Deyn PP,A novel presenilin 1 mutation associated with Pick's disease but not beta-amyloid plaques.Ann Neurol,2004.55(5):p.617-626.
172.Raux G,GR.,Thomas-Anterion C,Boulliat J,Verpillat P,Hannequin D,Brice A,Frebourg T,Campion D,Dementia with prominent frontotemporal features associated with L113P presenilin 1 mutation.Neurology.2000 Nov 28;,2000.55(10):p.1577-1578.
173.Cuzzocrea,S.,C.Thiemermann,and D.Salvemini,Potential therapeutic effect of antioxidant therapy in shock and inflammation.Curr Med Chem,2004.11(9):p.1147-62.
174.Kovacic,P.and J.D.Jacintho,Mechanisms of carcinogenesis:focus on oxidative stress and electron transfer.Curr Med Chem,2001.8(7):p.773-96.
175.Takano,H.,et al.,Oxidative stress-induced signal transduction pathways in cardiac myocytes:involvement of ROS in heart diseases.Antioxid Redox Signal,2003.5(6):p.789-94.
176.Zhu,X.,et al.,Oxidative stress signalling in Alzheimer's disease.Brain Res,2004.1000(1-2):p.32-9.
177.Emerit,J.,M.Edeas,and F.Bricaire,Neurodegenerative diseases and oxidative stress.Biomed Pharmacother,2004.58(1):p.39-46.
178.Perry,G,et al.,Oxidative damage in Alzheimer's disease:the metabolic dimension.Int J Dev Neurosci,2000.18(4-5):p.417-21.
179.Cottrell,D.A.,et al.,Mitochondrial enzyme-deficient hippocampal neurons and choroidal cells in AD.Neurology,2001.57(2):p.260-4.
180.Takashima,A.,et al.,Activation of tau protein kinase I/glycogen synthase kinase-3beta by amyloid beta peptide (25-35) enhances phosphorylation of tau in hippocampal neurons.Neurosci Res,1998.31(4):p.317-23.
181.Auld,D.S.,et al.,Alzheimer's disease and the basal forebrain cholinergic system:relations to beta-amyloid peptides,cognition,and treatment strategies.Prog Neurobiol,2002.68(3):p.209-45.
182.Brenner,D.E.,et al.,Relationship between cigarette smoking and Alzheimer's disease in a population-based case-control study.Neurology,1993.43(2):p.293-300.
183.Svensson,A.L.and A.Nordberg,Beta-estradiol attenuate amyloid beta-peptide toxicity via nicotinic receptors.Neuroreport,1999.10(17):p.3485-9.