人参皂苷Rb1通过抑制L-型电压门控钙通道的活性改善Aβ_（25-35）诱导的海马神经元钙平衡紊乱
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摘要
阿尔茨海默病(Alzheimer’s disease,AD)是一种以进行性认知功能损害为主要临床症状的慢性、进行性的神经系统变性疾病。β淀粉样蛋白(β-amyloid protein,Aβ)沉积引起的神经炎性斑块(Neurite plaques,NP)是AD的主要病理特征之一。Aβ具有通过β-折叠的片层结构形成凝聚态的特性,短肽Aβ25-35是其毒性片断。Aβ可通过多种途径发挥神经毒性作用,其中Aβ诱导的胞内[Ca2+]i浓度的升高具有关键性的作用。人参皂苷Rb1为人参的主要活性成分之一,我们前期的实验证实Rb1对AD具有神经保护作用,近期的研究发现人参皂苷Rb1可减少凝聚态Aβ25-35诱导的神经细胞钙浓度从而降低钙蛋白酶(calpain)活性,减轻tau蛋白磷酸化,保持微管稳定性。但是,Rb1减轻细胞内Ca2+浓度的机制仍不清楚,由于电压门控的钙通道及内质网钙库参与的钙调控在Aβ25-35诱导的细胞内钙超载中起重要作用,本研究拟从上述这两方面来探讨Rb1对钙超载影响的可能机制。
方法:应用全细胞膜片钳技术通过设定的不同刺激方案记录原代培养7d海马神经元上的电压门控的钙通道电流(voltage-gated calcium channel current ,VGCC)。利用细胞外灌流、细胞内液给药及预孵育等给药方式,同时分别应用各型钙通道特异性阻断剂或各种蛋白激酶的抑制剂,通过比较加药前后或不同组间电流幅度的变化探讨Aβ25-35对VGCC的调控及Rb1对Aβ25-35诱导的钙内流的作用机制。预先用钙高度特异性荧光探针Flou-3/AM负载海马神经元,进行荧光染色,利用激光扫描共聚焦显微镜观察在不同药物干预条件下海马神经元内游离钙离子荧光强度的变化探讨Aβ25-35对内质网钙库调控及Rb1对Aβ25-35诱导的内质网钙库释放的影响。
结果:(1)在原代培养的海马神经元上存在多种的钙电流成分(L、N、P/Q、T等),它们具有各自不同的药理学及动力学特性;急性给予10μmolL-1凝聚态Aβ25-35对VGCC没有影响;10μmolL-1凝聚态Aβ25-35预孵育3、6、12、24h后,各组电流均较对照组有不同程度的增加,并以预孵育3h记录到的高电压激活的钙电流(HVA-Ica)变化为著,而预孵育对细胞的膜电容没有影响。(2)L-型钙通道的特异性抑制剂nifedipine完全抑制了凝聚态Aβ25-35诱导的Ca2+通道电流的增加;N型钙通道特异性抑制剂ω-conotoxin GVIA及P/Q型通道特异性的抑制剂ω-agatoxin IVA均无法完全抑制凝聚态Aβ25-35诱导的Ca2+通道电流的增加。PKA抑制剂H-89部分抑制了Aβ预孵育组的电流,而MAPK抑制剂PD98059无法抑制Aβ诱导的电流的增大。(3)2、10、20μM各浓度组凝聚态Aβ25-35均增加了海马神经元胞内[Ca2+]i;IP3R的特异性抑制剂2-APB明显地抑制了胞内[Ca2+]i的增加,兰尼硷受体(RyR)的特异性抑制剂dantrolene却无法抑制。Aβ25-35作用1h后内质网钙容量即有明显下降,在作用24h后降低更为明显。在无细胞外钙情况下,磷脂酶C的抑制剂U73122部分抑制了Aβ25-35诱导的胞内[Ca2+]i的增加。(4)人参皂苷Rb1可以浓度依赖性的方式抑制海马神经元上VGCC,并且抑制了Aβ25-35诱导的VGCC。Nifedipine完全阻断了之前1μMRb1对Aβ25-35诱导的VGCC的抑制,而ω-conotoxin-GVIA、ω-agatoxin IVA等作用前后1μMRb1对Aβ25-35诱导的VGCC的抑制作用没有受到影响;Rb1使Aβ25-35作用的稳态失活曲线向左即超极化方向偏移,而对Aβ25-35诱导的VGCC的激活特性没有影响;cAMP的类似物Forskolin并没有消除10μM Rb1对VGCC的抑制,Rb1对Aβ25-35诱导的VGCC的抑制率亦没有被PKA/PKC抑制剂staurosporine所影响。在无细胞外钙情况下,各浓度组Rb1不能抑制Aβ25-35诱导的细胞内钙荧光强度的增强。
结论:凝聚态Aβ25-35可通过PKA系统对细胞膜上特定的钙通道进行磷酸化调控增大VGCC。Aβ25-35可通过IP3途径产生IP3作用于IP3R而引起内质网钙的释放,磷脂酶C的活化可能参与了上述过程。人参皂苷Rb1是一种钙通道阻滞剂,它通过选择性地作用于L-型电压门控的钙通道,影响钙通道的失活过程,即通过加速通道向失活态的转化抑制通道的活性从而抑制了Aβ25-35诱导的VGCC。Rb1对Aβ25-35诱导的细胞内钙的释放没有影响。以上可能是Rb1减轻Aβ25-35诱导的海马神经元钙超载的分子机制,也是人参在抗衰老及在治疗阿尔茨海默病中发挥药理作用的细胞和分子基础。
Alzheimer’s disease(AD) is a progressive neurodegenerative disease that is characterized by its typical clinical sympotoms of progressive cognitive impairment. The deposition of amyloidβprotein (Aβ), as insoluble fibrillar aggregates in neuritic plaque, is the dominant histological hallmark of Alzheimer’s disease. Aβtends to form its aggregate state throughβ-sheet lamellar structure, and Aβ25-35 is its toxic fragment. Aβexerts its neurotoxicity through a variety of ways, elevation of intracellular calcium may play a key role of all.Ginsenoside Rb1, one protopanaxadiol type saponin, is one of the most important active compounds of ginseng. Our previous experiments confirmed that Rb1 has neuroprotective effects for AD . Most recently we found that Rb1 could decrease the elevation of intracellular calcium induced by aggregated Aβ25-35 so as to inhibit the activity of calpain and lower the level of phosphorylation of tau and help stabilize microtube.However, the underlie mechanism by which Rb1 decreases the concentration of Ca2+ in cell remains unknown.Because voltage-gated calcium channel and endoplasmic reticulum calcium stores plays an important role in calcium overload in cells induced by Aβ25-35 therefore in this paper we probed into the possible mechanism of Rb1’s effect on calcium overload based on mechanisms of the two sides .
Method: VGCC was recorded in primary cultured hippocampal neurons (7 days in vitro, DIV7)by using whole cell configuration of patch clamp technique.Drug was applied by extracellular bath or adding in the pipette solution or pretreatment,and its effect was determined by comparing the amplitude of IHVA before and after the drug application(or among different groups).A variety of calcium channel blockers or specific protein kinase inhibitors were involved in it to examine the effect of Aβ25-35 on VGCC and the possible mechanism of Rb1’s effect.The hippocampal neurons were loaded with calcium-sensitive fluorescent indicator Fluo-3/AM. Intracellular calcium concentration ([Ca2+]i)changes were measured in different conditions of drug intervention by using laser scanning confocal microscopy so as to examine the effect of Aβ25-35 on endoplasmic reticulum calcium stores and the possible mechanism of Rb1’s effect on calcium release of endoplasmic reticulum induced by Aβ25-35.
Result: (1)There were multiple types of Ca2+ channel in primary cultured hippocampal neurons (L, N, P / Q, T, etc.), they could be distinguished on the basis of pharmacological and kinetic properties. Acute extracellular exposure of 10μmolL-1 aggregated Aβ25-35 has no effect on VGCC; However ICa of each group(aggregated Aβ25-35 preincubated for 3, 6, 12, 24h) all had augment compared to the control group with a pronounced effect in the preincubated-3h group. Preincubation with aggregated Aβdid not have an effect on whole-cell capacitance of hippocampal neurons compared to the control group.(2)Block of L-type Ca2+ channels by its specific inhibitor nifedipine completely prevent the current augmentation induced by preincubation with aggregated Aβ,however, block of N-type Ca2+ channels or P/Q-type Ca2+ channels by their specific inhibitorsω-conotoxin GVIA andω-agatoxin IVA,respectively,could not prevent the current augmentation induced by preincubation with aggregated Aβ. PKA specific inhibitor,H-89, partially inhibited calcium current in the preincubated group but MAPK specific inhibitor, PD98059, could not .(3) Groups of 2、10、20μM Aβ25-35 all increase [Ca2+]i in hippocampal neurons. 2-APB, an inhibitor of ER Ca2+ release through channels associated to IP3R, was shown to prevent the aggregated Aβ25-35-induced rise of [Ca2+]i, suggesting the involvement of Ca2+ release by ER. Treatment with aggregated Aβ25-35 for 1 h induce a significant decrease in the ER Ca2+ content (P<0.01), which was more pronounced 24 h after the addition of aggregated Aβ25-35. The increase in [Ca2+]i observed in aggregated Aβ25-35-treated cells was prevented by the PLC inhibitor U-73122 in the absence of extracellular Ca2+.(4)Ginsenoside Rb1 inhibited calcium channel current in hippocampal neurons in a dose-dependent manner and also had the inhibitory effect on VGCC induced by Aβ25-35. Nifedipine blocks Ginsenoside Rb1-sensitive VGCC induced by Aβ25-35 completely.However eitherω-conotoxin-GVIA(a selective blocker of N-type channels)orω-agatoxin IVA(a selective blocker of P/Q -type channels)could not dimininish Rb1-sensitive VGCC induced by Aβ25-35. Ginsenoside Rb1 induced a leftward shift of the steady-state inactivation curves of ICa to negative potential in the preincubated group without affecting its activation kinetics.The co-application of 10μmol/L Rb1 and forskolin did not cancel the reduction and the action of 10μmol/L Rb1 was not affected by staurosporine(a PKA / PKC inhibitor).
Conclusion:Aggregated Aβ25-35 increased VGCC by regulating the phosphorylation of specific cell membrane calcium channel via PKA. IP3 pathway involved in the early release of Ca2+ from ER induced by Aβ25-35, the activation of PLC may involve in the process. Ginsenoside Rb1 high selectively targeted L-type calcium channel and inhibited channel activity by accelerating it access to the state of inactivation.Rb1 did not affect release of intracellular calcium induced by Aβ25-35. The above may be its molecular mechanisms in alleviating calcium overload induced by Aβ25-35 and the cell basis of ginseng to play pharmacological role in the Anti-Aging and the treatment of Alzheimer's disease.
方法:应用全细胞膜片钳技术通过设定的不同刺激方案记录原代培养7d海马神经元上的电压门控的钙通道电流(voltage-gated calcium channel current ,VGCC)。利用细胞外灌流、细胞内液给药及预孵育等给药方式,同时分别应用各型钙通道特异性阻断剂或各种蛋白激酶的抑制剂,通过比较加药前后或不同组间电流幅度的变化探讨Aβ25-35对VGCC的调控及Rb1对Aβ25-35诱导的钙内流的作用机制。预先用钙高度特异性荧光探针Flou-3/AM负载海马神经元,进行荧光染色,利用激光扫描共聚焦显微镜观察在不同药物干预条件下海马神经元内游离钙离子荧光强度的变化探讨Aβ25-35对内质网钙库调控及Rb1对Aβ25-35诱导的内质网钙库释放的影响。
结果:(1)在原代培养的海马神经元上存在多种的钙电流成分(L、N、P/Q、T等),它们具有各自不同的药理学及动力学特性;急性给予10μmolL-1凝聚态Aβ25-35对VGCC没有影响;10μmolL-1凝聚态Aβ25-35预孵育3、6、12、24h后,各组电流均较对照组有不同程度的增加,并以预孵育3h记录到的高电压激活的钙电流(HVA-Ica)变化为著,而预孵育对细胞的膜电容没有影响。(2)L-型钙通道的特异性抑制剂nifedipine完全抑制了凝聚态Aβ25-35诱导的Ca2+通道电流的增加;N型钙通道特异性抑制剂ω-conotoxin GVIA及P/Q型通道特异性的抑制剂ω-agatoxin IVA均无法完全抑制凝聚态Aβ25-35诱导的Ca2+通道电流的增加。PKA抑制剂H-89部分抑制了Aβ预孵育组的电流,而MAPK抑制剂PD98059无法抑制Aβ诱导的电流的增大。(3)2、10、20μM各浓度组凝聚态Aβ25-35均增加了海马神经元胞内[Ca2+]i;IP3R的特异性抑制剂2-APB明显地抑制了胞内[Ca2+]i的增加,兰尼硷受体(RyR)的特异性抑制剂dantrolene却无法抑制。Aβ25-35作用1h后内质网钙容量即有明显下降,在作用24h后降低更为明显。在无细胞外钙情况下,磷脂酶C的抑制剂U73122部分抑制了Aβ25-35诱导的胞内[Ca2+]i的增加。(4)人参皂苷Rb1可以浓度依赖性的方式抑制海马神经元上VGCC,并且抑制了Aβ25-35诱导的VGCC。Nifedipine完全阻断了之前1μMRb1对Aβ25-35诱导的VGCC的抑制,而ω-conotoxin-GVIA、ω-agatoxin IVA等作用前后1μMRb1对Aβ25-35诱导的VGCC的抑制作用没有受到影响;Rb1使Aβ25-35作用的稳态失活曲线向左即超极化方向偏移,而对Aβ25-35诱导的VGCC的激活特性没有影响;cAMP的类似物Forskolin并没有消除10μM Rb1对VGCC的抑制,Rb1对Aβ25-35诱导的VGCC的抑制率亦没有被PKA/PKC抑制剂staurosporine所影响。在无细胞外钙情况下,各浓度组Rb1不能抑制Aβ25-35诱导的细胞内钙荧光强度的增强。
结论:凝聚态Aβ25-35可通过PKA系统对细胞膜上特定的钙通道进行磷酸化调控增大VGCC。Aβ25-35可通过IP3途径产生IP3作用于IP3R而引起内质网钙的释放,磷脂酶C的活化可能参与了上述过程。人参皂苷Rb1是一种钙通道阻滞剂,它通过选择性地作用于L-型电压门控的钙通道,影响钙通道的失活过程,即通过加速通道向失活态的转化抑制通道的活性从而抑制了Aβ25-35诱导的VGCC。Rb1对Aβ25-35诱导的细胞内钙的释放没有影响。以上可能是Rb1减轻Aβ25-35诱导的海马神经元钙超载的分子机制,也是人参在抗衰老及在治疗阿尔茨海默病中发挥药理作用的细胞和分子基础。
Alzheimer’s disease(AD) is a progressive neurodegenerative disease that is characterized by its typical clinical sympotoms of progressive cognitive impairment. The deposition of amyloidβprotein (Aβ), as insoluble fibrillar aggregates in neuritic plaque, is the dominant histological hallmark of Alzheimer’s disease. Aβtends to form its aggregate state throughβ-sheet lamellar structure, and Aβ25-35 is its toxic fragment. Aβexerts its neurotoxicity through a variety of ways, elevation of intracellular calcium may play a key role of all.Ginsenoside Rb1, one protopanaxadiol type saponin, is one of the most important active compounds of ginseng. Our previous experiments confirmed that Rb1 has neuroprotective effects for AD . Most recently we found that Rb1 could decrease the elevation of intracellular calcium induced by aggregated Aβ25-35 so as to inhibit the activity of calpain and lower the level of phosphorylation of tau and help stabilize microtube.However, the underlie mechanism by which Rb1 decreases the concentration of Ca2+ in cell remains unknown.Because voltage-gated calcium channel and endoplasmic reticulum calcium stores plays an important role in calcium overload in cells induced by Aβ25-35 therefore in this paper we probed into the possible mechanism of Rb1’s effect on calcium overload based on mechanisms of the two sides .
Method: VGCC was recorded in primary cultured hippocampal neurons (7 days in vitro, DIV7)by using whole cell configuration of patch clamp technique.Drug was applied by extracellular bath or adding in the pipette solution or pretreatment,and its effect was determined by comparing the amplitude of IHVA before and after the drug application(or among different groups).A variety of calcium channel blockers or specific protein kinase inhibitors were involved in it to examine the effect of Aβ25-35 on VGCC and the possible mechanism of Rb1’s effect.The hippocampal neurons were loaded with calcium-sensitive fluorescent indicator Fluo-3/AM. Intracellular calcium concentration ([Ca2+]i)changes were measured in different conditions of drug intervention by using laser scanning confocal microscopy so as to examine the effect of Aβ25-35 on endoplasmic reticulum calcium stores and the possible mechanism of Rb1’s effect on calcium release of endoplasmic reticulum induced by Aβ25-35.
Result: (1)There were multiple types of Ca2+ channel in primary cultured hippocampal neurons (L, N, P / Q, T, etc.), they could be distinguished on the basis of pharmacological and kinetic properties. Acute extracellular exposure of 10μmolL-1 aggregated Aβ25-35 has no effect on VGCC; However ICa of each group(aggregated Aβ25-35 preincubated for 3, 6, 12, 24h) all had augment compared to the control group with a pronounced effect in the preincubated-3h group. Preincubation with aggregated Aβdid not have an effect on whole-cell capacitance of hippocampal neurons compared to the control group.(2)Block of L-type Ca2+ channels by its specific inhibitor nifedipine completely prevent the current augmentation induced by preincubation with aggregated Aβ,however, block of N-type Ca2+ channels or P/Q-type Ca2+ channels by their specific inhibitorsω-conotoxin GVIA andω-agatoxin IVA,respectively,could not prevent the current augmentation induced by preincubation with aggregated Aβ. PKA specific inhibitor,H-89, partially inhibited calcium current in the preincubated group but MAPK specific inhibitor, PD98059, could not .(3) Groups of 2、10、20μM Aβ25-35 all increase [Ca2+]i in hippocampal neurons. 2-APB, an inhibitor of ER Ca2+ release through channels associated to IP3R, was shown to prevent the aggregated Aβ25-35-induced rise of [Ca2+]i, suggesting the involvement of Ca2+ release by ER. Treatment with aggregated Aβ25-35 for 1 h induce a significant decrease in the ER Ca2+ content (P<0.01), which was more pronounced 24 h after the addition of aggregated Aβ25-35. The increase in [Ca2+]i observed in aggregated Aβ25-35-treated cells was prevented by the PLC inhibitor U-73122 in the absence of extracellular Ca2+.(4)Ginsenoside Rb1 inhibited calcium channel current in hippocampal neurons in a dose-dependent manner and also had the inhibitory effect on VGCC induced by Aβ25-35. Nifedipine blocks Ginsenoside Rb1-sensitive VGCC induced by Aβ25-35 completely.However eitherω-conotoxin-GVIA(a selective blocker of N-type channels)orω-agatoxin IVA(a selective blocker of P/Q -type channels)could not dimininish Rb1-sensitive VGCC induced by Aβ25-35. Ginsenoside Rb1 induced a leftward shift of the steady-state inactivation curves of ICa to negative potential in the preincubated group without affecting its activation kinetics.The co-application of 10μmol/L Rb1 and forskolin did not cancel the reduction and the action of 10μmol/L Rb1 was not affected by staurosporine(a PKA / PKC inhibitor).
Conclusion:Aggregated Aβ25-35 increased VGCC by regulating the phosphorylation of specific cell membrane calcium channel via PKA. IP3 pathway involved in the early release of Ca2+ from ER induced by Aβ25-35, the activation of PLC may involve in the process. Ginsenoside Rb1 high selectively targeted L-type calcium channel and inhibited channel activity by accelerating it access to the state of inactivation.Rb1 did not affect release of intracellular calcium induced by Aβ25-35. The above may be its molecular mechanisms in alleviating calcium overload induced by Aβ25-35 and the cell basis of ginseng to play pharmacological role in the Anti-Aging and the treatment of Alzheimer's disease.
引文
[1]Ferri C,Prince M,Brayne C,et al.Global prevalence of dementia:a Delphi consensus study.Lancet,2005,366:2112-2117
[2]Demuro A, Mina E, Kayed R, et al. Calcium dysregulation and membrane disruption as a ubiquitous neurotoxic mechanism of soluble amyloid oligomers. J Biol Chem, 2005,280: 17294-17300.
[3]Lopez JR, Lyckman A, Oddo S, et al. Increased intraneuronal resting [Ca(2+)]i in adult Alzheimer's disease mice .J Neurochem , 2008,105:262-271.
[4]Ferreiro E, Oliveira CR, Pereira C, et al. Involvement of endoplasmic reticulum Ca2+? ? release through ryanodine and inositol 1,4,5-triphosphate receptors in the neurotoxic effects induced by the amyloid-beta peptide. J Neurosci Res, 2004, 76:872–880.
[5]Ilya Bezprozvanny ,Mark P Mattson.Neuronal calcium mishandling and the pathogenesis of Alzheimer’s disease.Cell,2008,31:454-463
[6]Rhee SK,Quist AP, Lal R,et al. Amyloid beta protein-(1–42) forms calcium-permeable, Zn2+-sensitive channel. J. Biol. Chem, 1998,273:13379–13382.
[7]Jang H, Zheng J, Nussinov R, et al. Models of beta-amyloid ion channels in the membrane suggest that channel formation in the bilayer is a dynamic process. Biophys J, 2007, 93:1938-1949.
[8]Mattson, MP. Pathways towards and away from Alzheimer’s disease. Nature ,2004,430: 631–639
[9]Leissring MA, Murphy MP, Mead TR, et al. A physiologic signaling role for the gsecretase-derived intracellular fragment of APP. Proc Natl Acad Sci U S A.,2002,99: 4697–4702
[10]Lee G, Pollard HB, Arispe N. Annexin 5 and apolipoprotein E2 protect against Alzheimer’s amyloid-β-peptide cytotoxicity by competitive inhibition at a common phosphatidylserine interaction site. Peptides,2002,23:1249–1263
[11]Nimmrich V, Grimm C, Draguhn A, et al. Amyloidβoligomers (Aβ(1-42) globulomer)suppress spontaneous synaptic activity by inhibition of P/Q-type calciumcurrents. J Neurosci,2008, 28:788–797
[12]Liu Q, Kawai H, Berg DK.β-Amyloid peptide blocks the response of a 7-containing nicotinic receptors on hippocampal neurons. Proc Natl Acad Sci,2001, 98:4734–4749
[13]Dougherty JJ, Wu J, Nichols RA.β-Amyloid regulation of presynaptic nicotinic receptors in rat hippocampus and neocortex. J Neurosci. ,2003,23: 6740–6747
[14]Guo, Q. Increased vulnerability of hippocampal neurons toxcitotoxic necrosis in presenilin-1 mutant knock-in mice. Nat Med,1999,5:101–106
[15]Stutzmann, GE. et al. Dysregulated IP3 signaling in cortical neurons of knock-in mice expressing an Alzheimer’s-linked mutation in presenilin1 results in exaggerated Ca2+ signals and altered membrane excitability. J Neurosci,2004,24 : 508–513
[16]Schneider, I. et al. Mutant presenilins disturb neuronal calcium homeostasis in the brain of transgenic mice, decreasing the threshold for excitotoxicity and facilitating long-term potentiation. J Biol Chem,2001,276:11539–11544
[17]Begley, JG. et al. Altered calcium homeostasis and mitochondrial dysfunction in cortical synaptic compartments of presenilin-1 mutant mice. J Neurochem,1999,72: 1030–1039
[18]黄天文,陈晓春,张静,等.钙蛋白酶-细胞周期依赖性蛋白激酶5通路参与β淀粉样蛋白25-35诱导的tau蛋白过度磷酸化.中华神经科杂志,2006,39:477-480.
[19]Ueda K, Shinohara S , Yagami T, et al.Amyloid beta protein potentiates Ca2+ influx through L-type voltage-sensitive Ca2+ channels: a possible involvement of free radicals.J Neurochem, 1997,68 :265-271.
[20]MF Cano-Abad, M. Villarroya, A.G. Garcia, et al. Ca2+ entry through L-type Ca2+ channels causes mitochondrial disruption and chromaffin cell death, J Biol Chem, 2001, 276: 39695-39704
[21]CX Luo, XJ Zhu, AX Zhang, et al. Blockade of L-type voltage-gated Ca2+ channel inhibits ischemia-induced neurogenesis by down-regulating iNOS expression in adult mouse.J Neurochem ,2005, 94:1077-1086
[22]Deisseroth K, Heist EK, Tsien RW. Translocation of calmodulinto the nucleussupports CREB phosphorylation in hippocampalneurons. Nature,1998,392: 198–202.
[23]Morgan SL, Teyler TJ. VDCCs and NMDARs underline twoforms of LTP in CA1 hippocampus in vivo. J Neurophysiol,1999, 82: 736–40.
[24]Bachurin, S. Antihistamine agent Dimebon as a novel neuroprotector and a cognition enhancer. Ann N Y Acad Sci. ,2001,939:425–435
[25]Grigorev VV, Dranyi OA, Bachurin SO, et al. Comparative study of action mechanisms of dimebon and memantine on AMPA- and NMDA-subtypes glutamate receptors in rat cerebral neurons. Bull Exp Biol Med,2003, 136: 474–477
[26]Rovira C, Arbez N, Mariani J, et al. Abeta(25-35) and Abeta(1-40) act on different calcium channels in CA1 hippocampal neurons. Biochem Biophys Res Commun, 2002 ,296:1317-1321.
[27]MacManus A, Ramsden M, Murray M, et al. Enancement of 45Ca2t influx and voltage-dependent Ca2tchannel activity byβ-amyloid (1–40) in rat cotical synaptosomes and cultured cortical neurons. Modulation by the proinflamatory cytokine interleukin-1beta.J Biol Chem,2000,275 :4713–4718.
[28]Zhang J, Wang H, Ye C, et al.ATP released by astrocytes mediates glutamatergic activity-dependent heterosynaptic suppression . Neuron ,2003,40:971–982.
[29]F Bretschneider, F Markwardt. Drug-dependent ion channel gating by application of concentration jumps using U-tube technique.Methods Enzymol, 1999, 294:180– 189.
[30]S Duan, IM Cooke. Selective inhibition of transient K+ current by La3+ in crab peptide-secretory neurons. J Neurophysiol , 1999, 81:1848–1855.
[31]Xu TL,Dong XP,Wang DS. N-methyl-D-aspartate enhancement of the glycine response in the rat sacral dorsal commissural neurons. Eur J Neurosci, 2000, 12: 1647-1653.
[32]Smirnov SV, Aaronson PI. Ca2+ currents in single myocytes from human mesenteric arteries:evidence for a physiological role of L-type channels. J Physiol, 1992,457:455-475.
[33]H Beck, R Steffens, CE Elger, et al.Voltage-dependent Ca2+ currents in epilepsy. Epilepsy Research, 1998, 32:321–332
[34]Kortekaas P, Wadman WJ .Development of HVA and LVA calcium currents in pyramidal CA1neurons in the hippocampus of the rat . Brain Res Dev Brain Res ,1997,101:139–147
[35]Kohr, G, Mody, et al.Endogenous intracellular calcium buffering and the activation:inactivation of HVA calcium currents in rat dentate gyrus granule cells. J Gen Physiol,1991,98:941–967.
[36]Nowycky, M C, Fox, et al. Three types of neuronal calcium channels with different calcium agonist sensitivity. Nature ,1985,316:440–443.
[37]Bean, BP. Classes of calcium channels in vertebrate cells. Annu. Rev. Physiol, 1989 ,51:367–384.
[38]Mintz, IM, Adams, et al. P-type calcium channels in rat central and peripheral neurons. Neuron, 1992,9:85–95
[39]Ahlijanian, M.K, Westenbroek, et al. Subunit structure and localization of dihydropyridine-sensitive calcium channels in mammalian brain, spinal cord, and retina. Neuron ,1990,4:819–832.
[40]Chin, H, Smith, et al. Expression of dihydropyridine-sensitive brain calcium channels in the rat central nervous system. FEBS Lett,1992,299:69–74.
[41]Lalo UV, Pankratov YV, Arndts D, et al. Omega-conotoxin GVIA potently inhibits the currents mediated by P2X receptors in rat DRG neurons. Brain ResBull , 2001, 54:507-512
[42]Feng ZP, Arnot MI, Doering CJ, et al. Calcium channel beta subunits differentially regulate the inhibition of N-type channels by individual Gbeta isoforms. J Biol Chem,2001,276: 45051-45058
[43]Stephens GJ, Morris NP, Fyffe RE, et al. The Cav2.1/alpha1A (P/Q-type) voltage-dependent calcium channel mediates inhibitory neurotransmission onto mouse cerebellar Purkinje cells. Eur J Neurosci,2001,13:1902-1912
[44]Eliot, LS, Johnston, et al. Multiple components of calcium current in acutely dissociated dentate gyrus granule neurons. J Neurophysiol , 1994,72: 762–777.
[45]Rovira C, Arbez N, Mariani J, et al.Aβ(25–35) and Aβ(1–40) act on different calcium channels in CA1 hippocampal neurons. Biochemical and BiophysicalResearch Communications , 2002, 296:1317-1321
[46]MacManus A, Ramsden M, Murray M, et al. Enancement of 45Ca2t influx and voltage-dependent Ca2t channel activity byβ-amyloid (1–40) in rat cotical synaptosomes and cultured cortical neurons. Modulation by the proinflamatory cytokine interleukin-1beta.J Biol Chem,2000,275 :4713–4718.
[47]林智颖,陈晓春,廖大清,等.β淀粉样肽25-35对原代培养的海马神经元电压门控钙通道电流的影响.中华神经科杂志,2007,40:659-662
[48]Ramsden M, Henderson Z, Pearson HA, et al. Modulation of Ca2+ channel currents in primary cultures of rat cortical neurones by amyloidβprotein (1–40) is dependent on solubility status. Brain Research , 2002, 956:254-261.
[49]Arispe N, Pollard HB, Rojas E, et al. Giant multilevel cation channels formed by Alzheimer disease amyloid beta-protein [A beta P-(1–40)] in bilayer membranes.Proc Natl Acad Sci USA ,1993,90:10573–10577.
[50]Silvia D,Thomas H,Norbert AD. beta–amyloid 25 to 35 is intercalated in anionic and zwitterionic lipid membranes to different extents.Biophys J,2002,83:2610-2616
[51]Qi JS, Qiao JT. Amyloidβ-protein fragment31-35 forms ion channels in membrane patches excised from rat hippocampal neurons. Neurosci, 2001, 105: 845 -852.
[52]Lee G, Pollard HB, Arispe N. Annexin 5 and apolipoprotein E2 protect against Alzheimer’s amyloid-β-peptide cytotoxicity by competitive inhibition at a common phosphatidylserine interaction site. Peptides ,2002,23:1249–1263
[53]Ekinci FJ, Malik KU , Shea TB, et al. Activation of the L voltage sensitive calcium channel by mitogen-activated protein (MAP)kinase following exposure of neuronal cells to beta-amyloid. MAPkinase mediates beta-amyloid-induced neurodegeneration. J Biol Chem, 1999, 274: 30322–30327.
[54]Sculptoreanu A, Scheuer T, Catterall WA,et al. Voltage-dependent potentiation of L-type Ca2+ channels due to phosphorylation by cAMP-dependent protein kinase. Nature,1993 ,364:240-243.
[55]EgeT Kavalali, KatherineS Hwang, MarkR Plummer,et al.cAMP-Dependent Enhancement of Dihydropyridine-Sensitive Calcium Channel Availability inHippocampal Neurons.Journal of Neuroscience, 1997, 17:5334–5348
[56]CHEN Lei,LIU Chang-Jin,TANG Ming,et al.Action of beta–amyloid peptide1-40 on IHVA and its modulation by ginkgolide B.Acta Physiologica Sinica,2006,58:14-20
[57]Berridge MJ, Lipp P, Bootman MD. Signal transduction. The calcium entry pas de deux. Science,2000,287:1604–1605.
[58]Finch EA, Turner TJ, Goldin SM.Calcium as a coagonist of inositol 1,4,5-trisphosphate-induced calcium release. Science,1991,252:443–446.
[59]YaoY, Parker I . Potentiation of inositol trisphosphate-induced Ca2+ mobilization in Xenopus oocytes by cytosolic Ca2+. J Physiol,1992,458:319–338.
[60]Friel DD, Tsien RW. A caffeine- and ryanodine-sensitive Ca2+ store in bull frog sympathetic neurones modulates effects of Ca2+ entry on [Ca2+]i. J Physiol ,1992, 450 :217–246.
[61]Singh IN, Sorrentino G, Kanfer JN. AmloidβProtein25-35 stimulation of Phospholipase C in LA-N-2 cells.J Neurochem, 1997, 69:252-258
[62]Dutta D .Mechanism of store-operated calcium entry. J Biosci ,2000,25:397–404.
[63]Hedin HL, Eriksson S, Fowler CJ. Human platelet calcium mobilisation in response to beta-amyloid (25–35): buffer dependency and unchanged response in Alzheimer’s disease. Neurochem Int,2000, 38:145–151.
[64]Hsueh-Meei Huang, Hsio-Chung Ott, Shon-Jean Hsieh. Blockage of amyloidβpeptide-induced cytosolic free calciumby fullerenol-1, carboxylate c60 in PC12 cells. Life Sciences, 2000,66 :1525-1533
[65]Lindholm D, Wootz H, Korhonen L ER stress and neurodegenerative diseases. Cell Death Differ ,2006,13:385–392.
[66]Ferreiro E, Resende R, Costa R, et al.An endoplasmic-reticulum-specific apoptotic pathway is involved in prion and amyloid-beta peptides neurotoxicity. Neurobiol Dis,2006,23:669–678.
[67]Resende R, Ferreiro E, Pereira C, et al. Neurotoxic effect of oligomeric and fibrillar species of amyloid-beta peptide 1-42: involvement of endoplasmic reticulum calcium release in oligomer-induced cell death .Neuroscience ,2008, 155:725–737
[68]Demuro A, Mina E, Kayed R, et al.Calcium Dysregulation and MembraneDisruption as a Ubiquitous Neurotoxic Mechanism of Soluble Amyloid Oligomers. J Biol Chem, 2005, 280:17294-300
[69]Anguiano M, Nowak RJ, Lansbury PT, et al.Protofibrillar islet amyloid polypeptide permeabilizes synthetic vesicles by a pore-like mechanism that may be relevant to type II diabetes .Biochemistry,2002,41: 11338–11343
[70]Relini A, Torrassa S, Rolandi R, et al. Monitoring the process of HypF fibrillization and liposome permeabilization by protofibrils. J Mol Biol,2004,338: 943–957
[71]Bucciantini M, Calloni G, Chiti F, et al.Prefibrillar amyloid protein aggregates share common features of cytotoxicity. J Biol Chem,2004,279: 31374–31382
[72]Blanchard B J, Chen A, Rozeboom LM, et al.Efficient reversal of Alzheimer's disease fibril formation and elimination of neurotoxicity by a small molecule. Proc Natl Acad Sci U S A,2004, 101: 14326–14332
[73]Guo Q, Furukawa K, Sopher BL, Alzheimer's PS-1 mutation perturbs calcium homeostasis and sensitizes PC12 cells to death induced by amyloid beta-peptide , 1996, Neuroreport 8 :379–383
[74]Mattson MP, Chan SL. Calcium orchestrates apoptosis. Nat Cell Biol,2003,5: 1041–1043
[75]曾育琦,陈晓春,朱元贵等,人参皂苷Rb1抑制β淀粉样蛋白25-35诱导的皮层神经元tau蛋白过度磷酸化,药学学报.2005,40(3):225-230
[76]李永坤,陈晓春,朱元贵等,人参皂苷Rb1减轻冈田酸诱导的大鼠海马神经元Tau蛋白过度磷酸化,生理学报. 2005, 57(2):154-160
[77]谢玉华,陈晓春,张静等,人参皂苷Rb1可能通过CDK5途径Aβ25-35诱导的胎鼠海马神经元Tau蛋白过度磷酸化,药学学报. 2007,42(8):828-832
[78]宋锦秋,陈晓春,张静等,人参皂苷Rb1通过JNK/p38 MAPK途径减轻Aβ25-35诱导的胎鼠皮层神经元tau蛋白过度磷酸化,药学学报,2008, 43 (1) : 29 - 34
[79]Xiaochun Chen, Tianwen Huang, Jing Zhang, et al. Involvement of calpain and p25 of CDK5 pathway in ginsenoside Rb1's attenuation ofβ-amyloid peptide25–35-induced tau hyperphosphorylation in cortical neurons. Brain Res, 2008, 1200:99-106
[80]Lee E, Kim S, Chung KC, et al.20(S)-ginsenoside Rh2, a newly identified active ingredient of ginseng, inhibits NMDA receptors in cultured rat hippocampal neurons. Eur J Pharmacol,2006, 536:69-77
[81]Choi S, Jung SY, Lee JH, et al. Effect of ginsenosides, active components of ginseng, on nicotinic acetylcholine receptor expressed in Xenopus oocytes. Eur J Pharmacol,2002,442: 37–45
[82]Sala F, Mulet J, Chol S, et al. Effects of ginsenoside Rg2 on human neuronal nicotinic acetylcholine receptors. J Pharm Exp Ther,2002,301: 1052–1059.
[83]Choi SE, Lee JH, Oh S, et al.Effects of ginsenoside Rg2 on the 5-HT3A receptor mediated ion current in Xenopus oocytes. Mol. Cells, 2003,15: 108–113.
[84]Sang Min Jeong, Jun-Ho Lee, Sunoh Kim, et al.Ginseng saponins induce store-operated calcium entry in Xenopus oocytes.British Journal of Pharmacology , 2004 , 142:585–593
[85]Kim S, Ahn K , Oh TH, et al.Inhibitory effect of ginsenosides on NMDA receptor mediated-signals in rat hippocampus neurons. Biochem Biophys Res Comm,2002, 296 : 247–254.
[86]Coon AL, Wallace DR, Mactutus CF, et al. L-type calcium channels in the hippocampus and cerebellum of Alzheimer’s disease brain tissue. Neurobiol Aging, 1999,20:597–603.
[87]Veng LM, Mesches MH, Browning MD. Age-related working memory impairment is correlated with increases in the L-type calcium channel proteinα1D (Cav1.3) in area CA1 of the hippocampus and both are ameliorated by chronic nimodipine treatment. Mol Brain Res ,2003,110:193–202.
[88]Thibault O, Hadley R, Landfield PW. Elevated postsynaptic [Ca2+]i and L-type calcium channel activity in aged hippocampal neurons: relationship to impaired synaptic plasticity. J Neurosci ,2001,21: 9744–56.
[89]H Fu, W Li, Y Lao, et al. Bis(7)-tacrine attenuates beta amyloid-induced neuronal apoptosis by regulating L-type calcium channels. J Neurochem,2006, 98 :1400-1410
[90]Mattson,M P,Cheng,et al.beta-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to itotoxicity. J Neurosci,1992,526:376–389.
[91]Pascale, A, Etcheberrigaray R.Calcium alterations in Alzheimer's disease: Pathophysiology models and therapeutic opportunities. Pharmacol Res,1999, 39: 81 -88
[92]Hung, KS , Hwang, et al. Calpain inhibitor inhibits p35-p25-Cdk5 activation, decreases tau hyperphosphorylation, and improves neurological function after spinal cord hemisection in rats. J Neuropathol Exp Neurol,2005,64 : 15–26.
[93]Choi S, Jung SY, Kim CH, et al. Effect of ginsenosides on voltage-dependent Ca2+ channel subtypes in bovine chromaffin cells. J Ethnopharmacol,2001, 74:75–81.
[94]Nah SY, Park HJ, Mccleskey EW. A trace component of ginseng that inhibits Ca2+ channels through a pertussis toxin-sensitive G protein. Proc Natl Acad Sci, 1995,92: 8739–8743.
[95]张文杰,钟国赣,江岩等,人参二醇组与三醇组皂甙对大鼠心室肌细胞钙通道阻滞作用的单通道分析,中国药理学报. 1994,15(2):173-176
[96]Toshihiko Katafuchi, Shumin Duan, Sachiko Take, et al. Modulation of glutamate-induced outward current by prostaglandin E2 in rat dissociated preoptic neurons. Brain Res, 2005, 1037:180–186.
[1]Sp?t A, Szanda G, Csordás G, et al.High- and low-calcium-dependent mechanisms of mitochondrial calcium signalling. Cell Calcium, 2008, 44: 51–63
[2]Hardy, J. A hundred years of Alzheimer’s disease research.Neuron, 2006, 52: 3–13
[3]Mattson MP ,Magnus T. Ageing and neuronal vulnerability. NatRev Neurosci,2006, 7: 278–294
[4]Murchison D,Griffith WH. Calcium buffering systems and calcium signaling in aged rat basal forebrain neurons. Aging Cell ,2007,6:297–305
[5]Brown MR, Geddes JW, Sullivan PG, et al. Brain region-specific, age-related, alterations in mitochondrial responses to elevated calcium.J Bioenerg Biomembr,2004,36: 401–406
[6]Toescu EC, Verkhratsky A, Landfield PW. et al. Ca2+ regulation and gene expression in normal brain aging. Trends Neurosci, 2004,27:614–620
[7]Poon HF, Shepherd HM, Reed TT, et al. Proteomics analysis provides insight intocaloric restriction mediated oxidation and expression of brain proteins associated with age-related impaired cellular processes: mitochondrial dysfunction, glutamate dysregulation and impaired protein synthesis.Neurobiol Aging ,2006,27: 1020–1034
[8]Blalock EM, Chen KC, Sharrow K, et al. Gene microarrays in hippocampal aging:statistical profiling identifies novel processes correlated with cognitive impairment. J Neurosci,2003,23: 3807–3819
[9]Emilsson L, Saetre P, Jazin E. Alzheimer’s disease: mRNA expression profiles of multiple patients show alterations of genes involved with calcium signaling. Neurobiol Dis ,2006,21: 618–625
[10]Mattson, MP. Pathways towards and away from Alzheimer’s disease. Nature ,2004,430: 631–639
[11]Meyer-Luehmann M, Spires-Jones TL, Prada C, et al. Rapid appearance and local toxicity of amyloid-βplaques in a mouse model of Alzheimer’s disease. Nature ,2008,451: 720–724
[12]Furukawa K, Barger SW, Blalock EM, et al. Activation of K+ channels and suppression of neuronal activity by secretedβ-amyloid-precursor protein. Nature,1996,379:74–78
[13]Leissring MA, Murphy MP, Mead TR, et al. A physiologic signaling role for the gsecretase-derived intracellular fragment of APP. Proc Natl Acad Sci U S A,2002,99:4697–4702
[14]Lee G, Pollard HB, Arispe N. Annexin 5 and apolipoprotein E2 protect against Alzheimer’s amyloid-β-peptide cytotoxicity by competitive inhibition at a commonphosphatidylserine interaction site. Peptides,2002,23:1249–1263
[15]Simakova O,Arispe NJ. The cell-selective neurotoxicity of the Alzheimer’s Aβpeptide is determined by surface phosphatidylserine and cytosolic ATP levels. Membrane binding is required for Aβtoxicity. J Neurosci, 2007, 27: 13719–13729
[16]Sahu SK, Gummadi SN, Manoj N, et al. Phospholipid scramblases: an overview. Arch Biochem Biophys,2007,462: 103–114
[17]Nimmrich V, Grimm C, Draguhn A, et al. Amyloidβoligomers (Aβ(1-42) globulomer)suppress spontaneous synaptic activity by inhibition of P/Q-type calcium currents. J Neurosci,2008,28: 788–797
[18]Liu Q, Kawai H, Berg DK.β-Amyloid peptide blocks the response of a 7-containing nicotinic receptors on hippocampal neurons. Proc Natl Acad Sci,2001,98:4734–4749
[19]Dougherty JJ, Wu J, Nichols RA.β-Amyloid regulation of presynaptic nicotinic receptors in rat hippocampus and neocortex. J Neurosci ,2003,23: 6740–6747
[20]Wang Y, Chan SL, Miele L, et al. Involvement of Notch signaling in hippocampalsynaptic plasticity. Proc Natl Acad Sci ,2004, 101:9458–9462
[21]Stutzmann GE, Caccamo A, LaFerla FM,et al. Dysregulated IP3 signaling in cortical neurons of knock-in mice expressing an Alzheimer’s-linked mutation in presenilin1 results in exaggerated Ca2+ signals and altered membrane excitability. J Neurosci,2004,24:508–513
[22]Green KN, Demuro A, Akbari Y, et al. SERCA pump activity is physiologically regulated by presenilin and regulates amyloidβproduction. J Cell Biol,2008, 181:1107–1116
[23]Cai C, Lin P, Cheung KH ,et al. The presenilin-2 loop peptide perturbs intracellular Ca2+ homeostasis and accelerates apoptosis. J Biol Chem ,2006, 281: 16649–16655
[24]Cheung KH, Shineman D, Müller M,et al. Mechanism of Ca2+ disruption in Alzheimer’s disease by presenilin regulation of InsP3 receptor channel gating. Neuron,2008,58:871–883
[25]Stutzmann GE, Smith I, Caccamo A ,et al. Enhanced ryanodine receptor recruitment contributes to Ca2+ disruptions in young, adult, and aged Alzheimer’s disease mice. J Neurosci ,2006,26: 5180–5189
[26]Tu H, Nelson O, Bezprozvanny A ,et al. Presenilins form ER Ca2+ leak channels, a function disrupted by familial Alzheimer’s disease-linked mutations. Cell ,2006,126:981–993
[27]Nelson O, Tu H, Lei T,et al. Familial Alzheimer disease-linked mutations specifically disrupt Ca2+ leak function of presenilin 1. J Clin Invest ,2007,117: 1230–1239
[28]Cedazo-Minguez A, Popescu BO, Ankarcrona M, et al. The presenilin 1δE9 mutation gives enhanced basal phospholipase C activity and a resultant increase in intracellular calcium concentrations. J Biol Chem,2002,277: 36646–36655
[29]Dumanchin C, Tournier I, Martin C, et al. Biological effects of four PSEN1 gene mutations causing Alzheimer disease with spastic paraparesis and cotton wool plaques. Hum Mutat,2006, 27: 1063
[30]Nixon RA. The calpains in aging and aging-related diseases.Ageing Res Rev,2003,2:407–418
[31]Botella-López A, Burgaya F, Gavín R, et al. Reelin expression and glycosylation patterns are altered in Alzheimer’s disease. Proc. Natl. Acad. Sci. U S A ,2006, 103: 5573–5578
[32]Furukawa K, Wang Y, Yao PJ ,et al. Alteration in calcium channel properties is responsible for the neurotoxic action of a familial frontotemporal dementia tau mutation. J Neurochem,2003, 87: 427–436
[33]Lazarov O, Lee M, Peterson DA,et al. Evidence that synaptically releasedβ-amyloid accumulates as extracellular deposits in the hippocampus of transgenic mice. J Neurosci,2002, 22: 9785–9793
[34]Spires-Jones TL, Meyer-Luehmann M, Osetek JD, et al. Impaired spine stability underlies plaque-related spine loss in an Alzheimer’s disease mouse model.Am J Pathol,2007,171:1304–1311
[35]Celsi F, Svedberg M, Unger C, et al.β-Amyloid causes downregulation of calcineurin in neurons through induction of oxidative stress. Neurobiol Dis,2007, 26:342–352
[36]Lacor PN, Buniel MC, Furlow PW, et al. Aβoligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer’s disease. J Neurosci,2007, 27: 796–807
[37]Palop JJ, Chin J, Roberson ED, et al. Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models ofAlzheimer’s disease. Neuron,2007, 55:697–711
[38]Priller C, Dewachter I, Vassallo N ,et al. Mutant presenilin 1 alters synaptic transmission in cultured hippocampal neurons. J Biol Chem ,2007,282: 1119–1127
[39]Haughey NJ, Nath A, Chan SL, et al. Disruption of neurogenesis by amyloidβ-peptide,and perturbed neural progenitor cell homeostasis, in models of Alzheimer’s disease. J Neurochem,2002, 83:1509–1524
[40]Huang, Y. Apolipoprotein E and Alzheimer disease. Neurology,2006,66: S79–S85
[41]Chen Y, Beffert U, Ertunc M,et al. Reelin modulates NMDA receptor activity in cortical neurons. J Neurosci,2005, 25: 8209–8216
[42]Chin J, Massaro CM, Palop JJ,et al. Reelin depletion in the entorhinal cortex of human amyloid precursor protein transgenic mice and humans with Alzheimer’s disease. J Neurosci,2007, 27:2727–2733
[43]Geula C, Bu J, Nagykery N ,et al. Loss of calbindin-D28k from aging human cholinergic basal forebrain: relation to neuronal loss. J Comp Neurol,2003 ,455:249–259
[44]Mishizen-Eberz AJ, Rissman RA, Carter TL, et al. Biochemical and molecular studies of NMDA receptor subunits NR1/2A/2B in hippocampal subregions throughout progression of Alzheimer’s disease pathology. Neurobiol Dis,2004,15: 80–92
[45]Lazarov O, Robinson J, Tang YP, et al. Environmental enrichment reduces Aβlevels and amyloid deposition in transgenic mice. Cell,2005,120: 701–713
[46]Wolf SA, Kronenberg G, Lehmann K, et al. Cognitive and physical activitydifferently modulate disease progression in the amyloid precursor protein (APP)-23 model of Alzheimer’s disease. Biol Psychiatry ,2006,60:1314–1323
[47]Halagappa VK, Guo Z, Pearson M, et al. Intermittent fasting and caloric restriction ameliorate age-related behavioral deficits in the tripletransgenic mouse model of Alzheimer’s disease. Neurobiol Dis ,2007,26:212–220
[48]Mattson MP, Maudsley S, Martin B ,et al. BDNF and 5-HT: a dynamic duo in agerelated neuronal plasticity and neurodegenerative disorders. Trends Neurosci ,2004,27: 589–594
[49]Janus C, Pearson J, McLaurin J, et al. Aβpeptide immunization reduces behavioural impairment and plaques in a model of Alzheimer’s disease. Nature ,2000,408:979–982
[50]Schmidt B, Baumann S, Braun HA,et al. Inhibitors and modulators ofβ- and gsecretase.Curr Top Med Chem,2006, 6: 377–392
[51]Lindholm D, Wootz H, Korhonen L. ER stress and neurodegenerative diseases.Cell Death Differ,2006,13: 385–392
[52]Chan SL, Fu W, Zhang P, et al. Herp stabilizes neuronal Ca2+ homeostasis and mitochondrial function during endoplasmic reticulum stress. J Biol Chem,2004,279: 28733–28743
[53]Thiffault C, Bennett JP Jr.Cyclical mitochondrial dcM fluctuations linked to electron transport, F0F1 ATP-synthase and mitochondrial Na+/Ca2+ exchange are reduced in Alzheimer’s disease cybrids. Mitochondrion ,2005,5: 109–119
[54]Chan SL, Liu D, Kyriazis GA, et al. Mitochondrial uncoupling protein-4 regulatecalcium homeostasis and sensitivity to store depletion-induced apoptosis in neural cells. J Biol Chem,2006,281: 37391–37403
[55]Lipton, SA. Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond. Nat Rev Drug Discov,2006, 5:160–170
[56]Bachurin, S. Antihistamine agent Dimebon as a novel neuroprotector and a cognition enhancer. Ann N Y Acad Sci ,2001,939:425–435
[57]Grigorev VV, Dranyi OA, Bachurin SO, et al. Comparative study of action mechanisms of dimebon and memantine on AMPA- and NMDA-subtypes glutamate receptors in rat cerebral neurons. Bull Exp Biol Med,2003, 136: 474–477
[1]Sato K,Kawashima S.Calpain function in the modulation of signal transduction molecules[J]. Biol.Chem,2001 ,382(5):743-51.
[2]Sorimachi H,Suzuki K.The structure of calpain[J]. J Biochem, 2001 ,129(5): 653-64.
[3]Goll DE, Thompson VF, Li H, et al. The calpain system[J]. Physiol Rev, 2003 ,83(3):731-801.
[4]Moldoveanu T, Hosfield CM, Lim D, et al.A Ca(2+)switch aligns the active site of calpain[J]. Cell,2002 ,108(5):649-60
[5]Schoenwaelder S.M.,Yuan Y.,Jackson SP. Calpain regulation of integrin alpha IIb beta 3 signaling in human platelets[J].Platelets,2000 ,11(4):189-98.
[6]Zalewska T, Thompson VF, Goll DE. Effect of phosphatidylinositol and inside-out erythrocyte vesicles on autolysis of mu- and m-calpain from bovine skeletal muscle[J]. Biochim Biophys Acta,2004,1693 (2):125-133.
[7]Rock MT, Dix AR, Brooks WH, et al. Beta1 integrin-mediated T cell adhesion and cell spreading are regulated by calpain[J]. Exp Cell Res,2000,261 (1):260-270.
[8]Glading A, Uberall F, Keyse SM, et al. Membrane proximal ERK signaling is required for M-calpain activation downstream of epidermal growth factor receptor signaling[J]. J Biol Chem,2001,276 (26):23341-23348
[9]Cong J,Thompson VF,Goll DE.Phosphorylation of the Calpains.Mol Biol Cell, 2000,11:386a,
[10]Glading A,Chang P,Lauffenburger DA, et al.Epidermal growth factor receptor activation of calpain is required for fibroblast motility and occurs via an ERK/MAPkinase signaling pathway[J]. J Biol Chem,2000,275(4):2390-8.
[11]Shiraha H,Glading A,Chou J,et al..Activation of m-calpain(calpain II)by epidermal growth factor is limited by protein kinase A phosphorylation of m-calpain[J].Mol.Cell Biol,2002,22(8):2716-27.
[12]Smith SD,Jia Z,Huynh KK, et al.Glutamate substitutions at a PKA consensus site are consistent with inactivation of calpain by phosphorylation[J].FEBS Lett, 2003 ,542(1-3):115-8.
[13]Dourdin N,Bhatt AK,Dutt P, et al.Reduced cell migration and disruption of the actin cytoskeleton in calpain-deficient embryonic fibroblasts[J].J Biol Chem, 2001, 276(51):48382-8.
[14]Wu HY, Yuen EY, Lu YF, et al. Regulation of N-methyl-D-aspartate receptors by calpain in cortical neurons[J]. J Biol Chem.,2005 ,280(22):21588-93.
[15]Vinade L,Petersen JD,DO K, et al.Activation of calpain may alter the postsynaptic density structure and modulate anchoring of NMDA receptors[J].Synapse,2001, 40 (4) : 302-9.
[16]LaFerla FM. Calcium dyshomeostasis and intracellular signalling in Alzheimer's disease[J].Nat Rev Neurosci,2002 ,3(11):862-72.
[17]Mattson MP,Chan SL. Neuronal and glial calcium signaling in Alzheimer's disease[J].Cell Calcium,2003 ,34(4-5):385-97.
[18]Fifre A, Sponne I, Koziel V, et al.Microtubule-associated protein MAP1A, MAP1B,and MAP2 proteolysis during soluble amyloid beta-peptide-induced neuronalapoptosis[J]. J Biol Chem ,2006,281(1):229-240
[19]Fang ZY, Liu SJ, Wang XC, et al: Effect of calpain on the degradation of tau in rat brain cortex extracts[J]. Prog Biochem Biophys,2003 ,30 (6):884-888
[20]Kusakawa G.,Saito T,Onuki R, et al.Calpain-dependent proteolytic cleavage of the p35 cyclin-dependent kinase 5 activator to p25[J].J Biol Chem, 2000 , 275(22): 17166- 72.
[21]Jamsa A, Backstrom A, Gustafsson E, et al.Glutamate treatment and p25 transfection increase Cdk5 mediated tau phosphorylation in SH-SY5Y cells[J]. Biochem Biophys Res Commun,2006, 345 (1): 324-31.
[22]Patzke H.,Tsai LH. Calpain-mediated cleavage of the cyclin-dependent kinase-5 activator p39 to p29[J].J.Biol.Chem,2002 ,277(10):8054-60.
[23]Veeranna, Kaji T, Boland B, et al. Calpain mediates calcium-induced activation of the erk1,2 MAPK pathway and cytoskeletal phosphorylation in neurons: relevance to Alzheimer's disease[J].Am J Pathol,2004,165(3):795-805.
[24]Ray SK,Fidan M,Nowak MW,et al.Oxidative Stress and Ca2+ influx upregulate calpain and induce apoptosis in PC12 cells.Brain Res,2000 ,852(2):326-34.
[25]Wang HG.,Pathan N,Ethell,et al. Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD.Science,1999,284 (5412):339-343
[26]Liu F,Grundke-Iqbal I, Iqbal K, et al.Truncation and activation of calcineurin A by calpain I in Alzheimer Disease brain. J.Biol.Chem., 2005 ,280(45):37755-37762
[27]Wu HY, Tomizawa K, Oda Y, et al.Critical role of calpain-mediated cleavage of calcineurin in excitotoxic neurodegeneration. J.Biol.Chem,2004 ,279(6):4929-40
[2]Demuro A, Mina E, Kayed R, et al. Calcium dysregulation and membrane disruption as a ubiquitous neurotoxic mechanism of soluble amyloid oligomers. J Biol Chem, 2005,280: 17294-17300.
[3]Lopez JR, Lyckman A, Oddo S, et al. Increased intraneuronal resting [Ca(2+)]i in adult Alzheimer's disease mice .J Neurochem , 2008,105:262-271.
[4]Ferreiro E, Oliveira CR, Pereira C, et al. Involvement of endoplasmic reticulum Ca2+? ? release through ryanodine and inositol 1,4,5-triphosphate receptors in the neurotoxic effects induced by the amyloid-beta peptide. J Neurosci Res, 2004, 76:872–880.
[5]Ilya Bezprozvanny ,Mark P Mattson.Neuronal calcium mishandling and the pathogenesis of Alzheimer’s disease.Cell,2008,31:454-463
[6]Rhee SK,Quist AP, Lal R,et al. Amyloid beta protein-(1–42) forms calcium-permeable, Zn2+-sensitive channel. J. Biol. Chem, 1998,273:13379–13382.
[7]Jang H, Zheng J, Nussinov R, et al. Models of beta-amyloid ion channels in the membrane suggest that channel formation in the bilayer is a dynamic process. Biophys J, 2007, 93:1938-1949.
[8]Mattson, MP. Pathways towards and away from Alzheimer’s disease. Nature ,2004,430: 631–639
[9]Leissring MA, Murphy MP, Mead TR, et al. A physiologic signaling role for the gsecretase-derived intracellular fragment of APP. Proc Natl Acad Sci U S A.,2002,99: 4697–4702
[10]Lee G, Pollard HB, Arispe N. Annexin 5 and apolipoprotein E2 protect against Alzheimer’s amyloid-β-peptide cytotoxicity by competitive inhibition at a common phosphatidylserine interaction site. Peptides,2002,23:1249–1263
[11]Nimmrich V, Grimm C, Draguhn A, et al. Amyloidβoligomers (Aβ(1-42) globulomer)suppress spontaneous synaptic activity by inhibition of P/Q-type calciumcurrents. J Neurosci,2008, 28:788–797
[12]Liu Q, Kawai H, Berg DK.β-Amyloid peptide blocks the response of a 7-containing nicotinic receptors on hippocampal neurons. Proc Natl Acad Sci,2001, 98:4734–4749
[13]Dougherty JJ, Wu J, Nichols RA.β-Amyloid regulation of presynaptic nicotinic receptors in rat hippocampus and neocortex. J Neurosci. ,2003,23: 6740–6747
[14]Guo, Q. Increased vulnerability of hippocampal neurons toxcitotoxic necrosis in presenilin-1 mutant knock-in mice. Nat Med,1999,5:101–106
[15]Stutzmann, GE. et al. Dysregulated IP3 signaling in cortical neurons of knock-in mice expressing an Alzheimer’s-linked mutation in presenilin1 results in exaggerated Ca2+ signals and altered membrane excitability. J Neurosci,2004,24 : 508–513
[16]Schneider, I. et al. Mutant presenilins disturb neuronal calcium homeostasis in the brain of transgenic mice, decreasing the threshold for excitotoxicity and facilitating long-term potentiation. J Biol Chem,2001,276:11539–11544
[17]Begley, JG. et al. Altered calcium homeostasis and mitochondrial dysfunction in cortical synaptic compartments of presenilin-1 mutant mice. J Neurochem,1999,72: 1030–1039
[18]黄天文,陈晓春,张静,等.钙蛋白酶-细胞周期依赖性蛋白激酶5通路参与β淀粉样蛋白25-35诱导的tau蛋白过度磷酸化.中华神经科杂志,2006,39:477-480.
[19]Ueda K, Shinohara S , Yagami T, et al.Amyloid beta protein potentiates Ca2+ influx through L-type voltage-sensitive Ca2+ channels: a possible involvement of free radicals.J Neurochem, 1997,68 :265-271.
[20]MF Cano-Abad, M. Villarroya, A.G. Garcia, et al. Ca2+ entry through L-type Ca2+ channels causes mitochondrial disruption and chromaffin cell death, J Biol Chem, 2001, 276: 39695-39704
[21]CX Luo, XJ Zhu, AX Zhang, et al. Blockade of L-type voltage-gated Ca2+ channel inhibits ischemia-induced neurogenesis by down-regulating iNOS expression in adult mouse.J Neurochem ,2005, 94:1077-1086
[22]Deisseroth K, Heist EK, Tsien RW. Translocation of calmodulinto the nucleussupports CREB phosphorylation in hippocampalneurons. Nature,1998,392: 198–202.
[23]Morgan SL, Teyler TJ. VDCCs and NMDARs underline twoforms of LTP in CA1 hippocampus in vivo. J Neurophysiol,1999, 82: 736–40.
[24]Bachurin, S. Antihistamine agent Dimebon as a novel neuroprotector and a cognition enhancer. Ann N Y Acad Sci. ,2001,939:425–435
[25]Grigorev VV, Dranyi OA, Bachurin SO, et al. Comparative study of action mechanisms of dimebon and memantine on AMPA- and NMDA-subtypes glutamate receptors in rat cerebral neurons. Bull Exp Biol Med,2003, 136: 474–477
[26]Rovira C, Arbez N, Mariani J, et al. Abeta(25-35) and Abeta(1-40) act on different calcium channels in CA1 hippocampal neurons. Biochem Biophys Res Commun, 2002 ,296:1317-1321.
[27]MacManus A, Ramsden M, Murray M, et al. Enancement of 45Ca2t influx and voltage-dependent Ca2tchannel activity byβ-amyloid (1–40) in rat cotical synaptosomes and cultured cortical neurons. Modulation by the proinflamatory cytokine interleukin-1beta.J Biol Chem,2000,275 :4713–4718.
[28]Zhang J, Wang H, Ye C, et al.ATP released by astrocytes mediates glutamatergic activity-dependent heterosynaptic suppression . Neuron ,2003,40:971–982.
[29]F Bretschneider, F Markwardt. Drug-dependent ion channel gating by application of concentration jumps using U-tube technique.Methods Enzymol, 1999, 294:180– 189.
[30]S Duan, IM Cooke. Selective inhibition of transient K+ current by La3+ in crab peptide-secretory neurons. J Neurophysiol , 1999, 81:1848–1855.
[31]Xu TL,Dong XP,Wang DS. N-methyl-D-aspartate enhancement of the glycine response in the rat sacral dorsal commissural neurons. Eur J Neurosci, 2000, 12: 1647-1653.
[32]Smirnov SV, Aaronson PI. Ca2+ currents in single myocytes from human mesenteric arteries:evidence for a physiological role of L-type channels. J Physiol, 1992,457:455-475.
[33]H Beck, R Steffens, CE Elger, et al.Voltage-dependent Ca2+ currents in epilepsy. Epilepsy Research, 1998, 32:321–332
[34]Kortekaas P, Wadman WJ .Development of HVA and LVA calcium currents in pyramidal CA1neurons in the hippocampus of the rat . Brain Res Dev Brain Res ,1997,101:139–147
[35]Kohr, G, Mody, et al.Endogenous intracellular calcium buffering and the activation:inactivation of HVA calcium currents in rat dentate gyrus granule cells. J Gen Physiol,1991,98:941–967.
[36]Nowycky, M C, Fox, et al. Three types of neuronal calcium channels with different calcium agonist sensitivity. Nature ,1985,316:440–443.
[37]Bean, BP. Classes of calcium channels in vertebrate cells. Annu. Rev. Physiol, 1989 ,51:367–384.
[38]Mintz, IM, Adams, et al. P-type calcium channels in rat central and peripheral neurons. Neuron, 1992,9:85–95
[39]Ahlijanian, M.K, Westenbroek, et al. Subunit structure and localization of dihydropyridine-sensitive calcium channels in mammalian brain, spinal cord, and retina. Neuron ,1990,4:819–832.
[40]Chin, H, Smith, et al. Expression of dihydropyridine-sensitive brain calcium channels in the rat central nervous system. FEBS Lett,1992,299:69–74.
[41]Lalo UV, Pankratov YV, Arndts D, et al. Omega-conotoxin GVIA potently inhibits the currents mediated by P2X receptors in rat DRG neurons. Brain ResBull , 2001, 54:507-512
[42]Feng ZP, Arnot MI, Doering CJ, et al. Calcium channel beta subunits differentially regulate the inhibition of N-type channels by individual Gbeta isoforms. J Biol Chem,2001,276: 45051-45058
[43]Stephens GJ, Morris NP, Fyffe RE, et al. The Cav2.1/alpha1A (P/Q-type) voltage-dependent calcium channel mediates inhibitory neurotransmission onto mouse cerebellar Purkinje cells. Eur J Neurosci,2001,13:1902-1912
[44]Eliot, LS, Johnston, et al. Multiple components of calcium current in acutely dissociated dentate gyrus granule neurons. J Neurophysiol , 1994,72: 762–777.
[45]Rovira C, Arbez N, Mariani J, et al.Aβ(25–35) and Aβ(1–40) act on different calcium channels in CA1 hippocampal neurons. Biochemical and BiophysicalResearch Communications , 2002, 296:1317-1321
[46]MacManus A, Ramsden M, Murray M, et al. Enancement of 45Ca2t influx and voltage-dependent Ca2t channel activity byβ-amyloid (1–40) in rat cotical synaptosomes and cultured cortical neurons. Modulation by the proinflamatory cytokine interleukin-1beta.J Biol Chem,2000,275 :4713–4718.
[47]林智颖,陈晓春,廖大清,等.β淀粉样肽25-35对原代培养的海马神经元电压门控钙通道电流的影响.中华神经科杂志,2007,40:659-662
[48]Ramsden M, Henderson Z, Pearson HA, et al. Modulation of Ca2+ channel currents in primary cultures of rat cortical neurones by amyloidβprotein (1–40) is dependent on solubility status. Brain Research , 2002, 956:254-261.
[49]Arispe N, Pollard HB, Rojas E, et al. Giant multilevel cation channels formed by Alzheimer disease amyloid beta-protein [A beta P-(1–40)] in bilayer membranes.Proc Natl Acad Sci USA ,1993,90:10573–10577.
[50]Silvia D,Thomas H,Norbert AD. beta–amyloid 25 to 35 is intercalated in anionic and zwitterionic lipid membranes to different extents.Biophys J,2002,83:2610-2616
[51]Qi JS, Qiao JT. Amyloidβ-protein fragment31-35 forms ion channels in membrane patches excised from rat hippocampal neurons. Neurosci, 2001, 105: 845 -852.
[52]Lee G, Pollard HB, Arispe N. Annexin 5 and apolipoprotein E2 protect against Alzheimer’s amyloid-β-peptide cytotoxicity by competitive inhibition at a common phosphatidylserine interaction site. Peptides ,2002,23:1249–1263
[53]Ekinci FJ, Malik KU , Shea TB, et al. Activation of the L voltage sensitive calcium channel by mitogen-activated protein (MAP)kinase following exposure of neuronal cells to beta-amyloid. MAPkinase mediates beta-amyloid-induced neurodegeneration. J Biol Chem, 1999, 274: 30322–30327.
[54]Sculptoreanu A, Scheuer T, Catterall WA,et al. Voltage-dependent potentiation of L-type Ca2+ channels due to phosphorylation by cAMP-dependent protein kinase. Nature,1993 ,364:240-243.
[55]EgeT Kavalali, KatherineS Hwang, MarkR Plummer,et al.cAMP-Dependent Enhancement of Dihydropyridine-Sensitive Calcium Channel Availability inHippocampal Neurons.Journal of Neuroscience, 1997, 17:5334–5348
[56]CHEN Lei,LIU Chang-Jin,TANG Ming,et al.Action of beta–amyloid peptide1-40 on IHVA and its modulation by ginkgolide B.Acta Physiologica Sinica,2006,58:14-20
[57]Berridge MJ, Lipp P, Bootman MD. Signal transduction. The calcium entry pas de deux. Science,2000,287:1604–1605.
[58]Finch EA, Turner TJ, Goldin SM.Calcium as a coagonist of inositol 1,4,5-trisphosphate-induced calcium release. Science,1991,252:443–446.
[59]YaoY, Parker I . Potentiation of inositol trisphosphate-induced Ca2+ mobilization in Xenopus oocytes by cytosolic Ca2+. J Physiol,1992,458:319–338.
[60]Friel DD, Tsien RW. A caffeine- and ryanodine-sensitive Ca2+ store in bull frog sympathetic neurones modulates effects of Ca2+ entry on [Ca2+]i. J Physiol ,1992, 450 :217–246.
[61]Singh IN, Sorrentino G, Kanfer JN. AmloidβProtein25-35 stimulation of Phospholipase C in LA-N-2 cells.J Neurochem, 1997, 69:252-258
[62]Dutta D .Mechanism of store-operated calcium entry. J Biosci ,2000,25:397–404.
[63]Hedin HL, Eriksson S, Fowler CJ. Human platelet calcium mobilisation in response to beta-amyloid (25–35): buffer dependency and unchanged response in Alzheimer’s disease. Neurochem Int,2000, 38:145–151.
[64]Hsueh-Meei Huang, Hsio-Chung Ott, Shon-Jean Hsieh. Blockage of amyloidβpeptide-induced cytosolic free calciumby fullerenol-1, carboxylate c60 in PC12 cells. Life Sciences, 2000,66 :1525-1533
[65]Lindholm D, Wootz H, Korhonen L ER stress and neurodegenerative diseases. Cell Death Differ ,2006,13:385–392.
[66]Ferreiro E, Resende R, Costa R, et al.An endoplasmic-reticulum-specific apoptotic pathway is involved in prion and amyloid-beta peptides neurotoxicity. Neurobiol Dis,2006,23:669–678.
[67]Resende R, Ferreiro E, Pereira C, et al. Neurotoxic effect of oligomeric and fibrillar species of amyloid-beta peptide 1-42: involvement of endoplasmic reticulum calcium release in oligomer-induced cell death .Neuroscience ,2008, 155:725–737
[68]Demuro A, Mina E, Kayed R, et al.Calcium Dysregulation and MembraneDisruption as a Ubiquitous Neurotoxic Mechanism of Soluble Amyloid Oligomers. J Biol Chem, 2005, 280:17294-300
[69]Anguiano M, Nowak RJ, Lansbury PT, et al.Protofibrillar islet amyloid polypeptide permeabilizes synthetic vesicles by a pore-like mechanism that may be relevant to type II diabetes .Biochemistry,2002,41: 11338–11343
[70]Relini A, Torrassa S, Rolandi R, et al. Monitoring the process of HypF fibrillization and liposome permeabilization by protofibrils. J Mol Biol,2004,338: 943–957
[71]Bucciantini M, Calloni G, Chiti F, et al.Prefibrillar amyloid protein aggregates share common features of cytotoxicity. J Biol Chem,2004,279: 31374–31382
[72]Blanchard B J, Chen A, Rozeboom LM, et al.Efficient reversal of Alzheimer's disease fibril formation and elimination of neurotoxicity by a small molecule. Proc Natl Acad Sci U S A,2004, 101: 14326–14332
[73]Guo Q, Furukawa K, Sopher BL, Alzheimer's PS-1 mutation perturbs calcium homeostasis and sensitizes PC12 cells to death induced by amyloid beta-peptide , 1996, Neuroreport 8 :379–383
[74]Mattson MP, Chan SL. Calcium orchestrates apoptosis. Nat Cell Biol,2003,5: 1041–1043
[75]曾育琦,陈晓春,朱元贵等,人参皂苷Rb1抑制β淀粉样蛋白25-35诱导的皮层神经元tau蛋白过度磷酸化,药学学报.2005,40(3):225-230
[76]李永坤,陈晓春,朱元贵等,人参皂苷Rb1减轻冈田酸诱导的大鼠海马神经元Tau蛋白过度磷酸化,生理学报. 2005, 57(2):154-160
[77]谢玉华,陈晓春,张静等,人参皂苷Rb1可能通过CDK5途径Aβ25-35诱导的胎鼠海马神经元Tau蛋白过度磷酸化,药学学报. 2007,42(8):828-832
[78]宋锦秋,陈晓春,张静等,人参皂苷Rb1通过JNK/p38 MAPK途径减轻Aβ25-35诱导的胎鼠皮层神经元tau蛋白过度磷酸化,药学学报,2008, 43 (1) : 29 - 34
[79]Xiaochun Chen, Tianwen Huang, Jing Zhang, et al. Involvement of calpain and p25 of CDK5 pathway in ginsenoside Rb1's attenuation ofβ-amyloid peptide25–35-induced tau hyperphosphorylation in cortical neurons. Brain Res, 2008, 1200:99-106
[80]Lee E, Kim S, Chung KC, et al.20(S)-ginsenoside Rh2, a newly identified active ingredient of ginseng, inhibits NMDA receptors in cultured rat hippocampal neurons. Eur J Pharmacol,2006, 536:69-77
[81]Choi S, Jung SY, Lee JH, et al. Effect of ginsenosides, active components of ginseng, on nicotinic acetylcholine receptor expressed in Xenopus oocytes. Eur J Pharmacol,2002,442: 37–45
[82]Sala F, Mulet J, Chol S, et al. Effects of ginsenoside Rg2 on human neuronal nicotinic acetylcholine receptors. J Pharm Exp Ther,2002,301: 1052–1059.
[83]Choi SE, Lee JH, Oh S, et al.Effects of ginsenoside Rg2 on the 5-HT3A receptor mediated ion current in Xenopus oocytes. Mol. Cells, 2003,15: 108–113.
[84]Sang Min Jeong, Jun-Ho Lee, Sunoh Kim, et al.Ginseng saponins induce store-operated calcium entry in Xenopus oocytes.British Journal of Pharmacology , 2004 , 142:585–593
[85]Kim S, Ahn K , Oh TH, et al.Inhibitory effect of ginsenosides on NMDA receptor mediated-signals in rat hippocampus neurons. Biochem Biophys Res Comm,2002, 296 : 247–254.
[86]Coon AL, Wallace DR, Mactutus CF, et al. L-type calcium channels in the hippocampus and cerebellum of Alzheimer’s disease brain tissue. Neurobiol Aging, 1999,20:597–603.
[87]Veng LM, Mesches MH, Browning MD. Age-related working memory impairment is correlated with increases in the L-type calcium channel proteinα1D (Cav1.3) in area CA1 of the hippocampus and both are ameliorated by chronic nimodipine treatment. Mol Brain Res ,2003,110:193–202.
[88]Thibault O, Hadley R, Landfield PW. Elevated postsynaptic [Ca2+]i and L-type calcium channel activity in aged hippocampal neurons: relationship to impaired synaptic plasticity. J Neurosci ,2001,21: 9744–56.
[89]H Fu, W Li, Y Lao, et al. Bis(7)-tacrine attenuates beta amyloid-induced neuronal apoptosis by regulating L-type calcium channels. J Neurochem,2006, 98 :1400-1410
[90]Mattson,M P,Cheng,et al.beta-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to itotoxicity. J Neurosci,1992,526:376–389.
[91]Pascale, A, Etcheberrigaray R.Calcium alterations in Alzheimer's disease: Pathophysiology models and therapeutic opportunities. Pharmacol Res,1999, 39: 81 -88
[92]Hung, KS , Hwang, et al. Calpain inhibitor inhibits p35-p25-Cdk5 activation, decreases tau hyperphosphorylation, and improves neurological function after spinal cord hemisection in rats. J Neuropathol Exp Neurol,2005,64 : 15–26.
[93]Choi S, Jung SY, Kim CH, et al. Effect of ginsenosides on voltage-dependent Ca2+ channel subtypes in bovine chromaffin cells. J Ethnopharmacol,2001, 74:75–81.
[94]Nah SY, Park HJ, Mccleskey EW. A trace component of ginseng that inhibits Ca2+ channels through a pertussis toxin-sensitive G protein. Proc Natl Acad Sci, 1995,92: 8739–8743.
[95]张文杰,钟国赣,江岩等,人参二醇组与三醇组皂甙对大鼠心室肌细胞钙通道阻滞作用的单通道分析,中国药理学报. 1994,15(2):173-176
[96]Toshihiko Katafuchi, Shumin Duan, Sachiko Take, et al. Modulation of glutamate-induced outward current by prostaglandin E2 in rat dissociated preoptic neurons. Brain Res, 2005, 1037:180–186.
[1]Sp?t A, Szanda G, Csordás G, et al.High- and low-calcium-dependent mechanisms of mitochondrial calcium signalling. Cell Calcium, 2008, 44: 51–63
[2]Hardy, J. A hundred years of Alzheimer’s disease research.Neuron, 2006, 52: 3–13
[3]Mattson MP ,Magnus T. Ageing and neuronal vulnerability. NatRev Neurosci,2006, 7: 278–294
[4]Murchison D,Griffith WH. Calcium buffering systems and calcium signaling in aged rat basal forebrain neurons. Aging Cell ,2007,6:297–305
[5]Brown MR, Geddes JW, Sullivan PG, et al. Brain region-specific, age-related, alterations in mitochondrial responses to elevated calcium.J Bioenerg Biomembr,2004,36: 401–406
[6]Toescu EC, Verkhratsky A, Landfield PW. et al. Ca2+ regulation and gene expression in normal brain aging. Trends Neurosci, 2004,27:614–620
[7]Poon HF, Shepherd HM, Reed TT, et al. Proteomics analysis provides insight intocaloric restriction mediated oxidation and expression of brain proteins associated with age-related impaired cellular processes: mitochondrial dysfunction, glutamate dysregulation and impaired protein synthesis.Neurobiol Aging ,2006,27: 1020–1034
[8]Blalock EM, Chen KC, Sharrow K, et al. Gene microarrays in hippocampal aging:statistical profiling identifies novel processes correlated with cognitive impairment. J Neurosci,2003,23: 3807–3819
[9]Emilsson L, Saetre P, Jazin E. Alzheimer’s disease: mRNA expression profiles of multiple patients show alterations of genes involved with calcium signaling. Neurobiol Dis ,2006,21: 618–625
[10]Mattson, MP. Pathways towards and away from Alzheimer’s disease. Nature ,2004,430: 631–639
[11]Meyer-Luehmann M, Spires-Jones TL, Prada C, et al. Rapid appearance and local toxicity of amyloid-βplaques in a mouse model of Alzheimer’s disease. Nature ,2008,451: 720–724
[12]Furukawa K, Barger SW, Blalock EM, et al. Activation of K+ channels and suppression of neuronal activity by secretedβ-amyloid-precursor protein. Nature,1996,379:74–78
[13]Leissring MA, Murphy MP, Mead TR, et al. A physiologic signaling role for the gsecretase-derived intracellular fragment of APP. Proc Natl Acad Sci U S A,2002,99:4697–4702
[14]Lee G, Pollard HB, Arispe N. Annexin 5 and apolipoprotein E2 protect against Alzheimer’s amyloid-β-peptide cytotoxicity by competitive inhibition at a commonphosphatidylserine interaction site. Peptides,2002,23:1249–1263
[15]Simakova O,Arispe NJ. The cell-selective neurotoxicity of the Alzheimer’s Aβpeptide is determined by surface phosphatidylserine and cytosolic ATP levels. Membrane binding is required for Aβtoxicity. J Neurosci, 2007, 27: 13719–13729
[16]Sahu SK, Gummadi SN, Manoj N, et al. Phospholipid scramblases: an overview. Arch Biochem Biophys,2007,462: 103–114
[17]Nimmrich V, Grimm C, Draguhn A, et al. Amyloidβoligomers (Aβ(1-42) globulomer)suppress spontaneous synaptic activity by inhibition of P/Q-type calcium currents. J Neurosci,2008,28: 788–797
[18]Liu Q, Kawai H, Berg DK.β-Amyloid peptide blocks the response of a 7-containing nicotinic receptors on hippocampal neurons. Proc Natl Acad Sci,2001,98:4734–4749
[19]Dougherty JJ, Wu J, Nichols RA.β-Amyloid regulation of presynaptic nicotinic receptors in rat hippocampus and neocortex. J Neurosci ,2003,23: 6740–6747
[20]Wang Y, Chan SL, Miele L, et al. Involvement of Notch signaling in hippocampalsynaptic plasticity. Proc Natl Acad Sci ,2004, 101:9458–9462
[21]Stutzmann GE, Caccamo A, LaFerla FM,et al. Dysregulated IP3 signaling in cortical neurons of knock-in mice expressing an Alzheimer’s-linked mutation in presenilin1 results in exaggerated Ca2+ signals and altered membrane excitability. J Neurosci,2004,24:508–513
[22]Green KN, Demuro A, Akbari Y, et al. SERCA pump activity is physiologically regulated by presenilin and regulates amyloidβproduction. J Cell Biol,2008, 181:1107–1116
[23]Cai C, Lin P, Cheung KH ,et al. The presenilin-2 loop peptide perturbs intracellular Ca2+ homeostasis and accelerates apoptosis. J Biol Chem ,2006, 281: 16649–16655
[24]Cheung KH, Shineman D, Müller M,et al. Mechanism of Ca2+ disruption in Alzheimer’s disease by presenilin regulation of InsP3 receptor channel gating. Neuron,2008,58:871–883
[25]Stutzmann GE, Smith I, Caccamo A ,et al. Enhanced ryanodine receptor recruitment contributes to Ca2+ disruptions in young, adult, and aged Alzheimer’s disease mice. J Neurosci ,2006,26: 5180–5189
[26]Tu H, Nelson O, Bezprozvanny A ,et al. Presenilins form ER Ca2+ leak channels, a function disrupted by familial Alzheimer’s disease-linked mutations. Cell ,2006,126:981–993
[27]Nelson O, Tu H, Lei T,et al. Familial Alzheimer disease-linked mutations specifically disrupt Ca2+ leak function of presenilin 1. J Clin Invest ,2007,117: 1230–1239
[28]Cedazo-Minguez A, Popescu BO, Ankarcrona M, et al. The presenilin 1δE9 mutation gives enhanced basal phospholipase C activity and a resultant increase in intracellular calcium concentrations. J Biol Chem,2002,277: 36646–36655
[29]Dumanchin C, Tournier I, Martin C, et al. Biological effects of four PSEN1 gene mutations causing Alzheimer disease with spastic paraparesis and cotton wool plaques. Hum Mutat,2006, 27: 1063
[30]Nixon RA. The calpains in aging and aging-related diseases.Ageing Res Rev,2003,2:407–418
[31]Botella-López A, Burgaya F, Gavín R, et al. Reelin expression and glycosylation patterns are altered in Alzheimer’s disease. Proc. Natl. Acad. Sci. U S A ,2006, 103: 5573–5578
[32]Furukawa K, Wang Y, Yao PJ ,et al. Alteration in calcium channel properties is responsible for the neurotoxic action of a familial frontotemporal dementia tau mutation. J Neurochem,2003, 87: 427–436
[33]Lazarov O, Lee M, Peterson DA,et al. Evidence that synaptically releasedβ-amyloid accumulates as extracellular deposits in the hippocampus of transgenic mice. J Neurosci,2002, 22: 9785–9793
[34]Spires-Jones TL, Meyer-Luehmann M, Osetek JD, et al. Impaired spine stability underlies plaque-related spine loss in an Alzheimer’s disease mouse model.Am J Pathol,2007,171:1304–1311
[35]Celsi F, Svedberg M, Unger C, et al.β-Amyloid causes downregulation of calcineurin in neurons through induction of oxidative stress. Neurobiol Dis,2007, 26:342–352
[36]Lacor PN, Buniel MC, Furlow PW, et al. Aβoligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer’s disease. J Neurosci,2007, 27: 796–807
[37]Palop JJ, Chin J, Roberson ED, et al. Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models ofAlzheimer’s disease. Neuron,2007, 55:697–711
[38]Priller C, Dewachter I, Vassallo N ,et al. Mutant presenilin 1 alters synaptic transmission in cultured hippocampal neurons. J Biol Chem ,2007,282: 1119–1127
[39]Haughey NJ, Nath A, Chan SL, et al. Disruption of neurogenesis by amyloidβ-peptide,and perturbed neural progenitor cell homeostasis, in models of Alzheimer’s disease. J Neurochem,2002, 83:1509–1524
[40]Huang, Y. Apolipoprotein E and Alzheimer disease. Neurology,2006,66: S79–S85
[41]Chen Y, Beffert U, Ertunc M,et al. Reelin modulates NMDA receptor activity in cortical neurons. J Neurosci,2005, 25: 8209–8216
[42]Chin J, Massaro CM, Palop JJ,et al. Reelin depletion in the entorhinal cortex of human amyloid precursor protein transgenic mice and humans with Alzheimer’s disease. J Neurosci,2007, 27:2727–2733
[43]Geula C, Bu J, Nagykery N ,et al. Loss of calbindin-D28k from aging human cholinergic basal forebrain: relation to neuronal loss. J Comp Neurol,2003 ,455:249–259
[44]Mishizen-Eberz AJ, Rissman RA, Carter TL, et al. Biochemical and molecular studies of NMDA receptor subunits NR1/2A/2B in hippocampal subregions throughout progression of Alzheimer’s disease pathology. Neurobiol Dis,2004,15: 80–92
[45]Lazarov O, Robinson J, Tang YP, et al. Environmental enrichment reduces Aβlevels and amyloid deposition in transgenic mice. Cell,2005,120: 701–713
[46]Wolf SA, Kronenberg G, Lehmann K, et al. Cognitive and physical activitydifferently modulate disease progression in the amyloid precursor protein (APP)-23 model of Alzheimer’s disease. Biol Psychiatry ,2006,60:1314–1323
[47]Halagappa VK, Guo Z, Pearson M, et al. Intermittent fasting and caloric restriction ameliorate age-related behavioral deficits in the tripletransgenic mouse model of Alzheimer’s disease. Neurobiol Dis ,2007,26:212–220
[48]Mattson MP, Maudsley S, Martin B ,et al. BDNF and 5-HT: a dynamic duo in agerelated neuronal plasticity and neurodegenerative disorders. Trends Neurosci ,2004,27: 589–594
[49]Janus C, Pearson J, McLaurin J, et al. Aβpeptide immunization reduces behavioural impairment and plaques in a model of Alzheimer’s disease. Nature ,2000,408:979–982
[50]Schmidt B, Baumann S, Braun HA,et al. Inhibitors and modulators ofβ- and gsecretase.Curr Top Med Chem,2006, 6: 377–392
[51]Lindholm D, Wootz H, Korhonen L. ER stress and neurodegenerative diseases.Cell Death Differ,2006,13: 385–392
[52]Chan SL, Fu W, Zhang P, et al. Herp stabilizes neuronal Ca2+ homeostasis and mitochondrial function during endoplasmic reticulum stress. J Biol Chem,2004,279: 28733–28743
[53]Thiffault C, Bennett JP Jr.Cyclical mitochondrial dcM fluctuations linked to electron transport, F0F1 ATP-synthase and mitochondrial Na+/Ca2+ exchange are reduced in Alzheimer’s disease cybrids. Mitochondrion ,2005,5: 109–119
[54]Chan SL, Liu D, Kyriazis GA, et al. Mitochondrial uncoupling protein-4 regulatecalcium homeostasis and sensitivity to store depletion-induced apoptosis in neural cells. J Biol Chem,2006,281: 37391–37403
[55]Lipton, SA. Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond. Nat Rev Drug Discov,2006, 5:160–170
[56]Bachurin, S. Antihistamine agent Dimebon as a novel neuroprotector and a cognition enhancer. Ann N Y Acad Sci ,2001,939:425–435
[57]Grigorev VV, Dranyi OA, Bachurin SO, et al. Comparative study of action mechanisms of dimebon and memantine on AMPA- and NMDA-subtypes glutamate receptors in rat cerebral neurons. Bull Exp Biol Med,2003, 136: 474–477
[1]Sato K,Kawashima S.Calpain function in the modulation of signal transduction molecules[J]. Biol.Chem,2001 ,382(5):743-51.
[2]Sorimachi H,Suzuki K.The structure of calpain[J]. J Biochem, 2001 ,129(5): 653-64.
[3]Goll DE, Thompson VF, Li H, et al. The calpain system[J]. Physiol Rev, 2003 ,83(3):731-801.
[4]Moldoveanu T, Hosfield CM, Lim D, et al.A Ca(2+)switch aligns the active site of calpain[J]. Cell,2002 ,108(5):649-60
[5]Schoenwaelder S.M.,Yuan Y.,Jackson SP. Calpain regulation of integrin alpha IIb beta 3 signaling in human platelets[J].Platelets,2000 ,11(4):189-98.
[6]Zalewska T, Thompson VF, Goll DE. Effect of phosphatidylinositol and inside-out erythrocyte vesicles on autolysis of mu- and m-calpain from bovine skeletal muscle[J]. Biochim Biophys Acta,2004,1693 (2):125-133.
[7]Rock MT, Dix AR, Brooks WH, et al. Beta1 integrin-mediated T cell adhesion and cell spreading are regulated by calpain[J]. Exp Cell Res,2000,261 (1):260-270.
[8]Glading A, Uberall F, Keyse SM, et al. Membrane proximal ERK signaling is required for M-calpain activation downstream of epidermal growth factor receptor signaling[J]. J Biol Chem,2001,276 (26):23341-23348
[9]Cong J,Thompson VF,Goll DE.Phosphorylation of the Calpains.Mol Biol Cell, 2000,11:386a,
[10]Glading A,Chang P,Lauffenburger DA, et al.Epidermal growth factor receptor activation of calpain is required for fibroblast motility and occurs via an ERK/MAPkinase signaling pathway[J]. J Biol Chem,2000,275(4):2390-8.
[11]Shiraha H,Glading A,Chou J,et al..Activation of m-calpain(calpain II)by epidermal growth factor is limited by protein kinase A phosphorylation of m-calpain[J].Mol.Cell Biol,2002,22(8):2716-27.
[12]Smith SD,Jia Z,Huynh KK, et al.Glutamate substitutions at a PKA consensus site are consistent with inactivation of calpain by phosphorylation[J].FEBS Lett, 2003 ,542(1-3):115-8.
[13]Dourdin N,Bhatt AK,Dutt P, et al.Reduced cell migration and disruption of the actin cytoskeleton in calpain-deficient embryonic fibroblasts[J].J Biol Chem, 2001, 276(51):48382-8.
[14]Wu HY, Yuen EY, Lu YF, et al. Regulation of N-methyl-D-aspartate receptors by calpain in cortical neurons[J]. J Biol Chem.,2005 ,280(22):21588-93.
[15]Vinade L,Petersen JD,DO K, et al.Activation of calpain may alter the postsynaptic density structure and modulate anchoring of NMDA receptors[J].Synapse,2001, 40 (4) : 302-9.
[16]LaFerla FM. Calcium dyshomeostasis and intracellular signalling in Alzheimer's disease[J].Nat Rev Neurosci,2002 ,3(11):862-72.
[17]Mattson MP,Chan SL. Neuronal and glial calcium signaling in Alzheimer's disease[J].Cell Calcium,2003 ,34(4-5):385-97.
[18]Fifre A, Sponne I, Koziel V, et al.Microtubule-associated protein MAP1A, MAP1B,and MAP2 proteolysis during soluble amyloid beta-peptide-induced neuronalapoptosis[J]. J Biol Chem ,2006,281(1):229-240
[19]Fang ZY, Liu SJ, Wang XC, et al: Effect of calpain on the degradation of tau in rat brain cortex extracts[J]. Prog Biochem Biophys,2003 ,30 (6):884-888
[20]Kusakawa G.,Saito T,Onuki R, et al.Calpain-dependent proteolytic cleavage of the p35 cyclin-dependent kinase 5 activator to p25[J].J Biol Chem, 2000 , 275(22): 17166- 72.
[21]Jamsa A, Backstrom A, Gustafsson E, et al.Glutamate treatment and p25 transfection increase Cdk5 mediated tau phosphorylation in SH-SY5Y cells[J]. Biochem Biophys Res Commun,2006, 345 (1): 324-31.
[22]Patzke H.,Tsai LH. Calpain-mediated cleavage of the cyclin-dependent kinase-5 activator p39 to p29[J].J.Biol.Chem,2002 ,277(10):8054-60.
[23]Veeranna, Kaji T, Boland B, et al. Calpain mediates calcium-induced activation of the erk1,2 MAPK pathway and cytoskeletal phosphorylation in neurons: relevance to Alzheimer's disease[J].Am J Pathol,2004,165(3):795-805.
[24]Ray SK,Fidan M,Nowak MW,et al.Oxidative Stress and Ca2+ influx upregulate calpain and induce apoptosis in PC12 cells.Brain Res,2000 ,852(2):326-34.
[25]Wang HG.,Pathan N,Ethell,et al. Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD.Science,1999,284 (5412):339-343
[26]Liu F,Grundke-Iqbal I, Iqbal K, et al.Truncation and activation of calcineurin A by calpain I in Alzheimer Disease brain. J.Biol.Chem., 2005 ,280(45):37755-37762
[27]Wu HY, Tomizawa K, Oda Y, et al.Critical role of calpain-mediated cleavage of calcineurin in excitotoxic neurodegeneration. J.Biol.Chem,2004 ,279(6):4929-40