ERα在青年大鼠去势后学习记忆障碍中的作用及机制
|
摘要
【背景】
双侧卵巢切除术（Ovariectomy,Ovx）简称去势又称为外科绝经(SurgicalMenopause)，伴随着雌激素水平的显著降低，该手术后女性会早于更年期绝经，患心血管、认知障碍和痴呆等疾病的风险增加；认知功能障碍在双侧卵巢切除术后表现尤为明显，主要表现为记忆力减退，工作能力下降。雌激素对大脑有神经保护性作用，主要通过雌激素受体（ER）发挥功能，雌激素受体，包括了雌激素受体alpha（ER）和雌激素受体beta（ER），在大脑中分布广泛。然而，雌激素受体在双侧卵巢切除术后认知功能障碍中的作用和机制尚不清楚。
【目的】
探讨双侧卵巢切除术引发认知功能障碍的分子机制，为外科绝经女性预防认知功能障碍提供新的信息，为药物研发提供分子靶点。
【方法】
本研究以双侧卵巢切除的3月龄雌性大鼠作为研究对象，首先将Sprague-Dawley (SD)大鼠随机分为假手术组（Sham）和去势组（Ovx），分别监测假手术组和去势组在去势后24小时、第1周、第2周、第4周、第8周5个不同时间点，雌激素受体在大脑海马区的变化。根据实验结果，选择去势后第7-8周作为下一步实验的检测时间。Sham组和Ovx组大鼠在术后第7周开始进行水迷宫训练（Morris Water Maze，MWM）连续学习7天,休息6天后在去势第8周的最后一天检测大鼠学习记忆的能力。行为学检测结束后，快速收集样品。为了证明ER在去势雌性大鼠学习记忆中的作用，又将大鼠分为假手术组、去势组、对照给药组（Ovx+Vehicle）组和PPT给药组（Ovx+PPT）组,PPT给药组每天皮下注射ER的激动剂PPT(1mg/kg/day),对照给药组大鼠给予等体积的媒介液，持续给药8周。经行为学水迷宫训练检测后，收集样品。用酶联免疫吸附试验（Enzyme-linked immunosorbent assay，Elisa）、免疫蛋白印迹（WesternBlot,WB）、免疫组织化学（Immunohistochemistry，IH）、高尔基染色（GolgiImpregnation）尼氏染色（Nissel Staining）等方法来检测雌激素水平、雌激素受体的表达、神经元、树突棘及学习记忆相关蛋白和激酶的表达与活性。
【结果】
1.双侧卵巢切除大鼠学习记忆障碍，并伴有海马ER水平下降，ER无明显变化；同时伴有海马神经元、树突棘及突触相关蛋白丢失（Synapsin，NR2A, GluR1）,以及伴有学习记忆相关激酶活性的降低(CaMK,Akt，ERK)；
2.双侧卵巢切除后及时补充雌激素受体激动剂PPT,显著改善双侧卵巢切除大鼠学习记忆能力、改善双侧卵巢切除大鼠海马区神经元的丢失及ER表达下降、改善双侧卵巢切除大鼠海马区树突棘及突触相关蛋白的丢失和学习记忆相关激酶活性的降低。同时PPT能改善维持双侧卵巢切除大鼠子宫的重量并防止体重的增加；
【结论】
ERα，而不是ERβ在双侧卵巢切除诱导的认知障碍中发挥重要作用，及时补充ER激动剂PPT为去势后改善学习记忆的有效治疗方式之一。
【背景】
有报道显示雌激素能通过抑制糖原合酶激酶-3（Glycogen synthase kinase-3,GSK-3）的活性改善阿尔茨海默病（Alzheimer's disease，AD）的病理特点。AD的两大病理特征为A的沉积及Tau蛋白的异常磷酸化，GSK-3参与了这两大病理特征的形成。雌激素可通过雌激素受体ER发挥神经保护性作用，ER是GSK-3的底物之一，GSK-3磷酸化ER的Ser118位点。双侧卵巢切除术后脑内GSK-3活性变化及在去势诱导学习记忆障碍中的作用尚不清楚。
【目的】
探讨去势后脑内GSK-3活性变化及在去势诱导学习记忆障碍中的作用，为预防卵巢切除术后认知功能障碍提供依据。
【方法】
本研究以双侧卵巢切除的3月龄(Sprague-Dawley，SD)雌性大鼠作为研究对象，首先检测去势组和假手术组GSK-3在去势大鼠海马区的活性及表达，及雌激素受体的活性改变。分别在去势后运用ER的激动剂PPT、GSK-3的抑制剂LiCl及联合运用PPT+LiCL，观察去势大鼠学习记忆的变化。将大鼠随机分为载体组（Ovx+Vehicle）、PPT组（Ovx+PPT）、LiCL组（Ovx+LiCl）及（Ovx+PPT+LiCl）组。通过水迷宫训练分别监测不同给药组去势后学习记忆能力的改变。行为学检测结束后，快速收集样品。通过免疫蛋白印迹、免疫组化、成份蛋白的提取、Golgi染色等检测方法，了解不同给药组治疗后雌激素受体及GSK-3的活性、表达在大脑海马区的变化及分布。
【结果】
1.去势大鼠海马GSK-3激活并表达增加；去势大鼠ER活性位点p-Ser118ER在细胞核表达增高；
2.PPT组、LiCl组及联合给药组能通过减少去势后ER的丢失和抑制激活GSK-3改善去势大鼠学习记忆的能力；PPT组、LiCl组及联合给药组能通过减少去势后ER的丢失和抑制激活GSK-3延缓突触的丢失；
【结论】
PPT联合LiCl处理能显著缓解去势大鼠空间认知障碍，并能预防雌激素缺乏诱导的神经元退行性变性。
Ovariectomy is known as―surgical menopause‖with decreased levels of estrogen in femalerodents. And its reported risks and adverse effects include cognitive impairment. In thebrain, estrogen exerts effects through its receptors, estrogen receptor (ER) and (ER).However, the mechanism of ER or ER in ovariectomy-induced cognitive impairmentneeds further investigation. Here, we observed that bilateral ovariectomized3-month-oldrats showed obvious spatial learning and memory deficit in Morris water maze withsignificant loss of neurons and synapses in the hippocampus. Meanwhile with the quicklydeclined serum estradiol levels, the expression of ER in hippocampus, but not ER, wasdecreased since1week after ovariectomy. Prompt4,4,4-(4-propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol (PPT) treatment (1mg/kg/day), anagonist of ER, improved spatial learning and memory ability of ovariectomized rats andrescued ovariectomy-induced neurons loss by keeping the expression of BCLxl, animportant anti-apoptosis protein. Furthermore, ER rescue also improvedovariectomy-induced the loss of hippocampal synapses and up-regulated synapstic proteins(synapsin, NR2A and GluR1) and activating CaMK, ERK, and Akt. Thus, these resultsdemonstrated that ER plays an important role in neuroprotection and that prompt ER rescue is effective to improving hippocampal-dependent cognition deficit afterovariectomy.
Long-term estrogen deprivation has a significantly high risk of cognitive dysfunction.Experimental and basic studies show a modulatory role of estrogens in the brain andsuggest their beneficial action in cognitive ability and memory of neurodegenerativediseases. Estrogen is exerts its effects via genomic signaling mediated by interaction withnuclear estrogen receptor. But the mechanism of estrogen receptor on brain is complicated.In previous research, we investigated the effect of estrogen receptor in brain ofovariectomized rats, the results shown us estrogen receptor (ER) was declined afterovariectomy. Here, we found that GSK-3, a key enzyme with complicated signalingpathway in Alzheimer’s disease was activated corresponding with increased phosphorylatedserine-118(p-Ser118ER, activated form of ER) afer ovariectomy, and the GSK-3levelalso was up-regulated. Then, we use an agonist of ER, PPT and inhibitor of GSK-3, LiClrespectively, or combine PPT with LiCl to find the relationship about ER and GSK-3after ovariectomy. In this study, we found that PPT or LiCl treatment improved the deficitsof cognitive ability and memory through activation of GSK-3regulated or was regulatedby ER rescued in ovariectomzied rats. These data indicated that ER and GSK3β maybetwo drug targets to preserve cognitive ability and memory after long-term ovariectomy.
双侧卵巢切除术（Ovariectomy,Ovx）简称去势又称为外科绝经(SurgicalMenopause)，伴随着雌激素水平的显著降低，该手术后女性会早于更年期绝经，患心血管、认知障碍和痴呆等疾病的风险增加；认知功能障碍在双侧卵巢切除术后表现尤为明显，主要表现为记忆力减退，工作能力下降。雌激素对大脑有神经保护性作用，主要通过雌激素受体（ER）发挥功能，雌激素受体，包括了雌激素受体alpha（ER）和雌激素受体beta（ER），在大脑中分布广泛。然而，雌激素受体在双侧卵巢切除术后认知功能障碍中的作用和机制尚不清楚。
【目的】
探讨双侧卵巢切除术引发认知功能障碍的分子机制，为外科绝经女性预防认知功能障碍提供新的信息，为药物研发提供分子靶点。
【方法】
本研究以双侧卵巢切除的3月龄雌性大鼠作为研究对象，首先将Sprague-Dawley (SD)大鼠随机分为假手术组（Sham）和去势组（Ovx），分别监测假手术组和去势组在去势后24小时、第1周、第2周、第4周、第8周5个不同时间点，雌激素受体在大脑海马区的变化。根据实验结果，选择去势后第7-8周作为下一步实验的检测时间。Sham组和Ovx组大鼠在术后第7周开始进行水迷宫训练（Morris Water Maze，MWM）连续学习7天,休息6天后在去势第8周的最后一天检测大鼠学习记忆的能力。行为学检测结束后，快速收集样品。为了证明ER在去势雌性大鼠学习记忆中的作用，又将大鼠分为假手术组、去势组、对照给药组（Ovx+Vehicle）组和PPT给药组（Ovx+PPT）组,PPT给药组每天皮下注射ER的激动剂PPT(1mg/kg/day),对照给药组大鼠给予等体积的媒介液，持续给药8周。经行为学水迷宫训练检测后，收集样品。用酶联免疫吸附试验（Enzyme-linked immunosorbent assay，Elisa）、免疫蛋白印迹（WesternBlot,WB）、免疫组织化学（Immunohistochemistry，IH）、高尔基染色（GolgiImpregnation）尼氏染色（Nissel Staining）等方法来检测雌激素水平、雌激素受体的表达、神经元、树突棘及学习记忆相关蛋白和激酶的表达与活性。
【结果】
1.双侧卵巢切除大鼠学习记忆障碍，并伴有海马ER水平下降，ER无明显变化；同时伴有海马神经元、树突棘及突触相关蛋白丢失（Synapsin，NR2A, GluR1）,以及伴有学习记忆相关激酶活性的降低(CaMK,Akt，ERK)；
2.双侧卵巢切除后及时补充雌激素受体激动剂PPT,显著改善双侧卵巢切除大鼠学习记忆能力、改善双侧卵巢切除大鼠海马区神经元的丢失及ER表达下降、改善双侧卵巢切除大鼠海马区树突棘及突触相关蛋白的丢失和学习记忆相关激酶活性的降低。同时PPT能改善维持双侧卵巢切除大鼠子宫的重量并防止体重的增加；
【结论】
ERα，而不是ERβ在双侧卵巢切除诱导的认知障碍中发挥重要作用，及时补充ER激动剂PPT为去势后改善学习记忆的有效治疗方式之一。
【背景】
有报道显示雌激素能通过抑制糖原合酶激酶-3（Glycogen synthase kinase-3,GSK-3）的活性改善阿尔茨海默病（Alzheimer's disease，AD）的病理特点。AD的两大病理特征为A的沉积及Tau蛋白的异常磷酸化，GSK-3参与了这两大病理特征的形成。雌激素可通过雌激素受体ER发挥神经保护性作用，ER是GSK-3的底物之一，GSK-3磷酸化ER的Ser118位点。双侧卵巢切除术后脑内GSK-3活性变化及在去势诱导学习记忆障碍中的作用尚不清楚。
【目的】
探讨去势后脑内GSK-3活性变化及在去势诱导学习记忆障碍中的作用，为预防卵巢切除术后认知功能障碍提供依据。
【方法】
本研究以双侧卵巢切除的3月龄(Sprague-Dawley，SD)雌性大鼠作为研究对象，首先检测去势组和假手术组GSK-3在去势大鼠海马区的活性及表达，及雌激素受体的活性改变。分别在去势后运用ER的激动剂PPT、GSK-3的抑制剂LiCl及联合运用PPT+LiCL，观察去势大鼠学习记忆的变化。将大鼠随机分为载体组（Ovx+Vehicle）、PPT组（Ovx+PPT）、LiCL组（Ovx+LiCl）及（Ovx+PPT+LiCl）组。通过水迷宫训练分别监测不同给药组去势后学习记忆能力的改变。行为学检测结束后，快速收集样品。通过免疫蛋白印迹、免疫组化、成份蛋白的提取、Golgi染色等检测方法，了解不同给药组治疗后雌激素受体及GSK-3的活性、表达在大脑海马区的变化及分布。
【结果】
1.去势大鼠海马GSK-3激活并表达增加；去势大鼠ER活性位点p-Ser118ER在细胞核表达增高；
2.PPT组、LiCl组及联合给药组能通过减少去势后ER的丢失和抑制激活GSK-3改善去势大鼠学习记忆的能力；PPT组、LiCl组及联合给药组能通过减少去势后ER的丢失和抑制激活GSK-3延缓突触的丢失；
【结论】
PPT联合LiCl处理能显著缓解去势大鼠空间认知障碍，并能预防雌激素缺乏诱导的神经元退行性变性。
Ovariectomy is known as―surgical menopause‖with decreased levels of estrogen in femalerodents. And its reported risks and adverse effects include cognitive impairment. In thebrain, estrogen exerts effects through its receptors, estrogen receptor (ER) and (ER).However, the mechanism of ER or ER in ovariectomy-induced cognitive impairmentneeds further investigation. Here, we observed that bilateral ovariectomized3-month-oldrats showed obvious spatial learning and memory deficit in Morris water maze withsignificant loss of neurons and synapses in the hippocampus. Meanwhile with the quicklydeclined serum estradiol levels, the expression of ER in hippocampus, but not ER, wasdecreased since1week after ovariectomy. Prompt4,4,4-(4-propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol (PPT) treatment (1mg/kg/day), anagonist of ER, improved spatial learning and memory ability of ovariectomized rats andrescued ovariectomy-induced neurons loss by keeping the expression of BCLxl, animportant anti-apoptosis protein. Furthermore, ER rescue also improvedovariectomy-induced the loss of hippocampal synapses and up-regulated synapstic proteins(synapsin, NR2A and GluR1) and activating CaMK, ERK, and Akt. Thus, these resultsdemonstrated that ER plays an important role in neuroprotection and that prompt ER rescue is effective to improving hippocampal-dependent cognition deficit afterovariectomy.
Long-term estrogen deprivation has a significantly high risk of cognitive dysfunction.Experimental and basic studies show a modulatory role of estrogens in the brain andsuggest their beneficial action in cognitive ability and memory of neurodegenerativediseases. Estrogen is exerts its effects via genomic signaling mediated by interaction withnuclear estrogen receptor. But the mechanism of estrogen receptor on brain is complicated.In previous research, we investigated the effect of estrogen receptor in brain ofovariectomized rats, the results shown us estrogen receptor (ER) was declined afterovariectomy. Here, we found that GSK-3, a key enzyme with complicated signalingpathway in Alzheimer’s disease was activated corresponding with increased phosphorylatedserine-118(p-Ser118ER, activated form of ER) afer ovariectomy, and the GSK-3levelalso was up-regulated. Then, we use an agonist of ER, PPT and inhibitor of GSK-3, LiClrespectively, or combine PPT with LiCl to find the relationship about ER and GSK-3after ovariectomy. In this study, we found that PPT or LiCl treatment improved the deficitsof cognitive ability and memory through activation of GSK-3regulated or was regulatedby ER rescued in ovariectomzied rats. These data indicated that ER and GSK3β maybetwo drug targets to preserve cognitive ability and memory after long-term ovariectomy.
引文
Acosta, JI, Mayer, L, Talboom, JS, Zay, et al.(2009) Premarin improves memory,prevents scopolamine-induced amnesia and increases number of basal forebrain cholineacetyltransferase positive cells in middle-aged surgically menopausal rats. Hormones andBehavior55(3):454-464.
Andersen, K, Launer, LJ, Dewey, ME, Letenneur, L, et al.(1999) Gender differences inthe incidence of AD and vascular dementia: The EURODEM Studies. EURODEMIncidence Research Group. Neurology,53(9):1992-1997.
Bethea, CL, Smith, AW, Centeno, ML, Reddy, AP (2011) Long-term ovariectomydecreases serotonin neuron number and gene expression in free ranging macaques.Neuroscience192:675-688.
Bonomo, SM, Rigamonti, AE, Giunta, M, Galimberti, D, et al.(2009) Menopausaltransition: a possible risk factor for brain pathologic events. Neurobiology of Aging30(1):71-80.
Brinton, R D (2005) Investigative models for determining hormone therapy-inducedoutcomes in brain: evidence in support of a healthy cell bias of estrogen action. Annals ofthe New York Academy of Sciences.1052,57-74.
Carroll, JC, Pike, CJ (2008) Selective estrogen receptor modulators differentially regulateAlzheimer-like changes in female3xTg-AD mice. Endocrinology149(5):2607-2611.
Choleris, E, Gustafsson, JA, Korach, KS, Muglia, LJ, et al.(2003) Anestrogen-dependent four-gene micronet regulating social recognition: a study with oxytocinand estrogen receptor-alpha and-beta knockout mice. Proceedings of the National Academyof Sciences USA100(10):6192-6197.
Choleris, E, Kavaliers, M, Pfaff, DW (2004) Functional genomics of social recognition.Journal of Neuroendocrinology16(4):383-389.
Choleris, E, Ogawa, S, Kavaliers, M, Gustafsson, JA, et al.(2006) Involvement ofestrogen receptor alpha, beta and oxytocin in social discrimination: A detailed behavioralanalysis with knockout female mice. Genes Brain and Behavior5(7):528-539.
Cordey, M, Pike, CJ (2005) Neuroprotective properties of selective estrogen receptoragonists in cultured neurons. Brain Research1045(1-2):217-223.
Correia, SC, Santos, RX, Cardoso, S, Carvalho, C, et al.(2010) Effects of estrogen inthe brain: is it a neuroprotective agent in Alzheimer's disease? Current Aging Science3(2):113-126.
Dubal, DB, Zhu, H, Yu, J, Rau, SW, et al.(2001) Estrogen receptor alpha, not beta, is acritical link in estradiol-mediated protection against brain injury. Proceedings of theNational Academy of Sciences USA41483198.
Daniel, JM, Bohacek, J (2010) The critical period hypothesis of estrogen effects oncognition: Insights from basic research. Biochim Biophys Acta1800(10):1068-1076.
Espeland, MA, Rapp, SR, Shumaker, SA, Brunner, R, et al.(2004) Conjugated equineestrogens and global cognitive function in postmenopausal women: Women's HealthInitiative Memory Study. JAMA291(24):2959-2968.
Foster, TC (2012) Role of estrogen receptor alpha and beta expression and signaling oncognitive function during aging. Hippocampus22(4):656-69.
Frye, CA, Duffy, CK, Walf, AA (2007) Estrogens and progestins enhance spatial learningof intact and ovariectomized rats in the object placement task. Neurobiology of Learningand Memory88(2):208-216.
Gleason, C E,Cholerton, B, Carlsson, C M, Johnson, S C, et al.(2005) Neuroprotective effects of female sex steroids in humans: current controversies and futuredirections. Cellular and Molecular Life Sciences.62,299-312.
Gordon, A, Aguilar, R, Garrido-Gracia, JC, Guil-Luna, S, et al.(2009) Activation ofestrogen receptor-alpha induces gonadotroph progesterone receptor expression and actiondifferently in young and middle-aged ovariectomized rats. Human Reproduction,24(10):2618-2628.
Le Saux, M, Estrada-Camarena, E, Di Paolo, T (2006) Selective estrogen receptor-alphabut not-beta agonist treatment modulates brainalpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. Journal ofNeuroscience Research84(5):1076-1084.
LeBlanc, ES, Janowsky, J, Chan, BK, Nelson, HD (2001) Hormone replacement therapyand cognition: systematic review and meta-analysis. JAMA285(11):1489-1499.
Lewis, DK, Johnson, AB, Stohlgren, S, Harms, A, et al.(2008) Effects of estrogenreceptor agonists on regulation of the inflammatory response in astrocytes from young adultand middle-aged female rats. Journal of Neuroimmunology195(1-2):47-59.
Li, C, Brake, WG, Romeo, RD, Dunlop, JC, et al.(2004) Estrogen alters hippocampaldendritic spine shape and enhances synaptic protein immunoreactivity and spatial memoryin female mice. Proceedings of the National Academy of Sciences USA101(7):2185-2190.
Li, J, Siegel, M, Yuan, M, Zeng, Z, et al.(2011) Estrogen enhances neurogenesis andbehavioral recovery after stroke. Journal of Cerebral Blood Flow Metabolism31(2):413-425.
Liu, F, Day, M, Muniz, LC, Bitran, D, et al.(2008) Activation of estrogen receptor-betaregulates hippocampal synaptic plasticity and improves memory. Nature Neuroscience,11(3):334-343.
McEwen, BS, Alves, SE (1999) Estrogen actions in the central nervous system. EndocrineReviews20(3):279-307.
McEwen, B, Akama, K, Alves, S, Brake, WG, et al.(2001) Tracking the estrogen receptorin neurons: implications for estrogen-induced synapse formation. Proceedings of theNational Academy of Sciences U S A,98(13):7093-7100.
McEwen, B (2002) Estrogen actions throughout the brain. Recent Progress in HormoneResearch.57,357-384.
Mitra, SW, Hoskin, E, Yudkovitz, J, Pear, L, et al.(2003) Immunolocalization ofestrogen receptor beta in the mouse brain: comparison with estrogen receptor alpha.Endocrinology144(5):2055-2067.
Moult, P R,Harvey,J (2008) Hormonal regulation of hippocampal dendritic morphologyand synaptic plasticity. Cell adhesion&migration4,269-275.
Moriarty, K, Kim, KH, Bender, JR (2006) Minireview: estrogen receptor-mediated rapidsignaling. Endocrinology147(12):5557-5563.
Morissette, M, Le Saux, M, D Astous, M, Jourdain, S, et al.(2008a) Contribution ofestrogen receptors alpha and beta to the effects of estradiol in the brain. The Journal ofSteroid Biochemistry and Molecular Biology108(3-5):327-338.
Morissette, M, Le Saux, M, Di Paolo, T (2008b) Effect of oestrogen receptor alpha andbeta agonists on brain N-methyl-D-aspartate receptors. Journal of Neuroendocrinology20(8):1006-1014.
Morrison, JH (2011) A mechanism emerges for the critical period hypothesis for estrogentreatment. Proceedings of the National Academy of Sciences USA108(35):14375-14376.
Mukai, H, Kimoto, T, Hojo, Y, Kawato, S, et al.(2010) Modulation of synaptic plasticityby brain estrogen in the hippocampus. Biochimica et Biophysica Acta1800(10):1030-1044.
O'Neill, EE, Blewett, AR, Loria, PM, Greene, GL (2008) Modulation of alphaCaMKIIsignaling by rapid ERalpha action. Brain Research1222:1-17.
Pike, CJ, Carroll, JC, Rosario, ER, Barron, AM (2009) Protective actions of sex steroidhormones in Alzheimer's disease. Frontiers in Neuroendocrinology30(2):239-258.
Pompili, A, Arnone, B, Gasbarri, A (2012) Estrogens and memory in physiological andneuropathological conditions. Psychoneuroendocrinology.(Epub ahead of print)
Rissman, EF, Heck, AL, Leonard, JE, Shupnik, MA, et al.(2002) Disruption of estrogenreceptor beta gene impairs spatial learning in female mice. Proceedings of the NationalAcademy of Sciences USA99(6):3996-4001.
Rocca, WA, Bower, JH, Maraganore, DM, Ahlskog, JE, et al.(2007) Increased risk ofcognitive impairment or dementia in women who underwent oophorectomy beforemenopause. Neurology69(11):1074-1083.
Rocca, WA, Grossardt, BR, Shuster, LT (2010) Oophorectomy, menopause, estrogen, andcognitive aging: the timing hypothesis. Neurodegenerative Diseases7(1-3):163-166.
Ramon-Molinier, E.(1970) The Golgi-Cox technique, In: Nauta WJH., Ebbesson SOE.(Eds.)―Contemporary research methods in neuroanatomy‖pp:106-131. Springer, NY.
Sawai, T, Bernier, F, Fukushima, T, Hashimoto, T, et al.(2002) Estrogen induces a rapidincrease of calcium-calmodulin-dependent protein kinase II activity in the hippocampus.Brain Research,950(1-2):308-311.
Sherwin, BB, Henry, J F (2008) Brain aging modulates the neuroprotective effects ofestrogen on selective aspects of cognition in women: A critical review. Frontiers inNeuroendocrinology.29,88-113.
Sherwin, BB (2009) Estrogen therapy: is time of initiation critical for neuroprotection?Nature Review Endocrinology5(11):620-627.
Shughrue, PJ, Lane, MV, Merchenthaler, I (1997) Comparative distribution of estrogenreceptor-alpha and-beta mRNA in the rat central nervous system. Journal of ComparativeNeurology388(4):507-525.
Shumaker, SA, Legault, C, Kuller, L, Rapp, SR, et al.(2004) Conjugated equineestrogens and incidence of probable dementia and mild cognitive impairment inpostmenopausal women: Women's Health Initiative Memory Study. JAMA291(24):2947-2958.
Shuster, LT, Gostout, BS, Grossardt, BR, Rocca, WA (2008) Prophylactic oophorectomyin premenopausal women and long-term health. Menopause International14(3):111-116.
Simpkins, JW, Perez, E, Xiaofei Wang, ShaoHua Yang, et al.(2009) Review: Thepotential for estrogens in preventing Alzheimer's disease and vascular dementia.Therapeutic Advances in Neurological Disorders2(1):31-49.
Smith, CC, McMahon, LL (2005) Estrogen-induced increase in the magnitude oflong-term potentiation occurs only when the ratio of NMDA transmission to AMPAtransmission is increased. Journal of Neuroscience25(34):7780-7791.
Smith, CC, Vedder, LC, Nelson, AR, Bredemann, TM, et al.(2010) Duration of estrogendeprivation, not chronological age, prevents estrogen's ability to enhance hippocampalsynaptic physiology. Proceedings of the National Academy of Sciences USA107(45):19543-19548.
Stout Steele, M, Bennett, RA (2011) Clinical Technique: Dorsal Ovariectomy in Rodents.Journal of Exotic Pet Medicine20(3):222-226.
Suzuki, S, Brown, CM, Dela, CC, Yang, E, et al.(2007) Timing of estrogen therapy afterovariectomy dictates the efficacy of its neuroprotective and antiinflammatory actions.Proceedings of the National Academy of Sciences USA104(14):6013-6018.
Thakur, MK, Sharma, PK (2006) Aging of brain: role of estrogen. NeurochemicalResearch31(11):1389-1398.
Srivastava, DP, Woolfrey, KM, Liu, F, Brandon, NJ, Penzes, P (2010) Estrogenreceptor ss activity modulates synaptic signaling and structure. Journal of Neuroscience,30(40):13454-13460.
Thakur, MK, Sharma, PK (2006) Aging of brain: role of estrogen. NeurochemicalResearch31(11):1389-1398.
Tiwari-Woodruff, S, Morales, LB, Lee, R, Voskuhl, RR (2007) Differentialneuroprotective and antiinflammatory effects of estrogen receptor (ER)alpha and ERbetaligand treatment. Proceedings of the National Academy of Sciences USA104(37):14813-14818.
Turgeon, JL, Carr, MC, Maki, PM, Mendelsohn, ME, et al.(2006) Complex actions ofsex steroids in adipose tissue, the cardiovascular system, and brain: Insights from basicscience and clinical studies. Endocrine Reviews,27(6):575-605.
Vegeto, E, Belcredito, S, Etteri, S, Ghisletti, S, Brusadelli, A, et al.(2003) Estrogenreceptor-alpha mediates the brain antiinflammatory activity of estradiol. Proceedings of theNational Academy of Sciences USA100(16):9614-9619.
Vegeto, E, Belcredito, S, Ghisletti, S, Meda, C, et al.(2006) The endogenous estrogenstatus regulates microglia reactivity in animal models of neuroinflammation. Endocrinology147(5):2263-2272.
Walf, AA, Paris, JJ, Rhodes, ME, Simpkins, JW, et al.(2011) Divergent mechanisms fortrophic actions of estrogens in the brain and peripheral tissues. Brain Research1379:119-136.
Waters, EM, Mitterling, K, Spencer, JL, Mazid, S, et al.(2009) Estrogen receptor alphaand beta specific agonists regulate expression of synaptic proteins in rat hippocampus.Brain Research1290:1-11.
Wang, L, Andersson, S, Warner, M, Gustafsson, JA (2003) Estrogen receptor (ER)betaknockout mice reveal a role for ERbeta in migration of cortical neurons in the developingbrain. Proceedings of the National Academy of Sciences USA,100(2):703-708.
Woolley, C S, Gould, E,Frankfurt, M, McEwen, B S (1990) Naturally occurringfuctuation in dendritic spine density on adult hippocampal pyramidal neurons. Journal ofNeuroscience10,4035-4039.
Woolley, C S (2007) Acute effects of estrogen on neuronal physiology. Annual Review ofPharmacology and Toxicology47,657-680.
Yang, LC, Zhang, QG, Zhou, CF, Yang, F, et al.(2010) Extranuclear estrogen receptorsmediate the neuroprotective effects of estrogen in the rat hippocampus. PLoS One5(5):e9851.
Yildirim, M, Janssen, WG, Lou, WY, Akama, KT, et al.(2011) Effects of estrogen andaging on the synaptic distribution of phosphorylated Akt-immunoreactivity in the CA1region of the female rat hippocampus. Brain Research,1379:98-108.
Zandi, PP, Carlson, MC, Plassman, BL, Welsh-Bohmer, KA, et al.(2002) Hormonereplacement therapy and incidence of Alzheimer disease in older women: the Cache CountyStudy. JAMA288(17):2123-2129.
Zhang, QG, Han, D, Wang, RM, Dong, Y, et al.(2011) C terminus of Hsc70-interactingprotein (CHIP)-mediated degradation of hippocampal estrogen receptor-alpha and thecritical period hypothesis of estrogen neuroprotection. Proceedings of the NationalAcademy of Sciences USA108(35): E617-E624.
Zhang, QG, Raz, L, Wang, R, Han, D, et al.(2009) Estrogen attenuates ischemicoxidative damage via an estrogen receptor alpha-mediated inhibition of NADPH oxidaseactivation. Journal of Neuroscience29(44):13823-13836.
Zhao, L, Yao, J, Mao, Z, Chen, S, et al.(2011)17β-Estradiol regulates insulin-degradingenzyme expression via an ERβ/PI3-K pathway in hippocampus: Relevance to Alzheimer'sprevention. Neurobiology of Aging32(11):1949-1963.
1. Ali A, Hoeflich KP, Woodgett JR.(2001) Glycogen Synthase Kinase-3: Properties,Functions, and Regulation Chemical Reviews101,8
2.Carol A Grimes, Richard S Jope (2001)The multifaceted roles of glycogen synthasekinase3in cellular signaling Progress in Neurobiology65,391–426
3. Goodenough S, Schleusner D, Pietrzik C, Skutella T, et al.(2005) Glycogen synthasekinase3β links neuroprotection by17β-estradiol to key Alzheimer processes Neuroscience132,581–589
4. Fe′lix Herna′ndez, Jesu′s Avila (2008) The role of glycogen synthase kinase3in theearly stages ofAlzheimers’disease FEBS Letters582,3848–3854
5. Hernández F, de Barreda EG, Fuster-Matanzo A, Go i-Oliver P, et al.(2009) Therole of GSK3in Alzheimer disease Brain Research Bulletin80,248–250
6. Hernández F, Gómez de Barreda E, Fuster-Matanzo A, Lucas JJ, et al.(2010) GSK3:A possible link between beta amyloid peptide and tau protein Experimental Neurology223(2):322-5.
7. Akihiko Takashima (2009) Drug Development Targeting the Glycogen SynthaseKinase-3β (GSK-3β)-Mediated Signal Transduction Pathway:Role of GSK-3β in AdultBrain Journal of Pharmacological Sciences109,174-178
8. Y. Balaramana, A. R. Limayea, A.I.Leveyb, S. Srinivasana (2006) Glycogen synthasekinase3and Alzheimer’s disease: pathophysiological and therapeutic significanceCellular and Molecular Life Sciences63,1226–1235
9.Zandi, PP, Carlson, MC, Plassman, BL, Welsh-Bohmer, KA, et al.(2002) Hormonereplacement therapy and incidence of Alzheimer disease in older women: the Cache CountyStudy. JAMA288(17):2123-2129.
10. Jean Grisouard, Doris Mayer (2009) Specifc involvement of glycogen synthasekinase-3in the function and activity of sex steroid hormone receptors reveals thecomplexity of their regulation Journal of Steroid Biochemistry&Molecular Biology117,87–92
11. Jean Grisouard, Senad Medunjanin, Alexander Hermani, Ashish Shukla, et al.(2005) Glycogen Synthase Kinase-3Protects Estrogen Receptor from ProteasomalDegradation and Is Required for Full Transcriptional Activity of the Receptor MolecularEndocrinology21(10):2427–2439
12. Senad Medunjanin, Alexander Hermani, Barbara De Servi, Jean Grisouard, et al.(2005) Glycogen Synthase Kinase-3Interacts with and Phosphorylates Estrogen Receptorand Is Involved in the Regulation of Receptor Activity The Journal of BiologicalChemistry3006–33014
13. Beaulieu, J.M., Gainetdinov, R.R., Caron, M.G (2007) The Akt-GSK-3signalingcascade in the actions of dopamine Trends in Pharmacological Sciences28,166—172.
14. Alimohamad, H., Rajakumar, N., Seah, YH, Rushlow W.(2005) Antipsychotics alterthe protein expression levels of beta-catenin and GSK-3in the rat medial prefrontal cortexand striatum Biological Psychiatry57,533-542.
15. Cardona-Gomez, P, Perez M. Avila, J., Garcia-Segura, L.M., Wandosell, F (2004)Estradiol inhibits GSK3and regulates interaction of estrogen receptors GSK3, and beta-catenin in the hippocampus Molecular and Cellular Neuroscience25,363-373.
16. Shumaker, SA, Legault, C, Kuller, L, Rapp, SR, et al.(2004) Conjugated equineestrogens and incidence of probable dementia and mild cognitive impairment inpostmenopausal women: Women's Health Initiative Memory Study. JAMA291(24):2947-2958.
17.Shuster, LT, Gostout, BS, Grossardt, BR, Rocca, WA (2008) Prophylacticoophorectomy in premenopausal women and long-term health. Menopause International14(3):111-116.
18. Simpkins, JW, Perez, E, Xiaofei Wang, ShaoHua Yang, et al.(2009) Review: Thepotential for estrogens in preventing Alzheimer's disease and vascular dementia.Therapeutic Advances in Neurological Disorders2(1):31-49.
19.Morissette, M, Le Saux, M, Di Paolo, T (2008b) Effect of oestrogen receptor alphaand beta agonists on brain N-methyl-D-aspartate receptors. Journal of Neuroendocrinology20(8):1006-1014.
20. Morrison, JH (2011) A mechanism emerges for the critical period hypothesis forestrogen treatment. Proceedings of the National Academy of Sciences USA108(35):14375-14376.
21. Mukai, H, Kimoto, T, Hojo, Y, Kawato, S, et al.(2010) Modulation of synapticplasticity by brain estrogen in the hippocampus. Biochim Biophys Acta1800(10):1030-1044.
1Walf AA, Paris JJ, Rhodes ME, Simpkins JW, Frye CA (2011) Divergent mechanismsfor trophic actions of estrogens in the brain and peripheral tissues. Brain Resarch16:1379:119-36.
2Li J, Siegel M, Yuan M, Zeng Z, Finnucan L, Persky R, Hurn PD, McCullough LD (2011)Estrogen enhances neurogenesis and behavioral recovery after stroke. Journal ofCerebral Blood Flow&Metabolism31(2):413-25.
3Suzuki S, Brown CM, Dela Cruz CD, Yang E, Bridwell DA, Wise PM (2007) Timingof estrogen therapy after ovariectomy dictates the efficacy of its neuroprotective and antiinflammatory actions. Proc. Natl Acad. Sci. USA3:104(14):6013-8
4Correia SC, Santos RX, Cardoso S, Carvalho C, Santos MS, Oliveira CR, Moreira PI（2010）Effects of Estrogen in the Brain: Is it a Neuroprotective Agent in Alzheimer’sDisease? Current Aging Science3:113-126
5Walter A. Rocca, Brandon R. Grossardt, Lynne T. Shuster（2010）Oophorectomy,Meno-pause, Estrogen, and Cognitive Aging: The Timing Hypothesis Neuro-degenerative Dis7:163–166
6Zhang, QG, Han, D, Wang, RM, Dong, Y, Yang, F, Vadlamudi, RK, Brann, DW (2011)C terminus of Hsc70-interacting protein (CHIP)-mediated degradation ofhippocampal estrogen receptor-alpha and the critical period hypothesis of estrogenneuroprotection. Proc. Natl Acad. Sci. USA108(35): E617-E624.
7Zhang, QG, Raz, L, Wang, R, Han, D, De Sevilla, L, Yang, F, Vadlamudi, RK, Brann,DW (2009) Estrogen attenuates ischemic oxidative damage via an estrogen receptoralpha-mediated inhibition of NADPH oxidase activation. Journal of Neuroscience,29(44):13823-13836.
8Andjelkovic, AV, Pachter, JS (1998) Central nervous system endothelium in neuro-inflammatory, neuroinfectious, and neurodegenerative disease. Journal ofNeuroscience Research,51(4):423-430.
9Floyd, RA (1999) Neuroinflammatory processes are important in neurodegenerativediseases: an hypothesis to explain the increased formation of reactive oxygen andnitrogen species as major factors involved in neurodegenerative disease development.Free Radic Biol Med,26(9-10):1346-1355.
10Spence, RD, Voskuhl, RR (2012) Neuroprotective effects of estrogens and androgensin CNS inflammation and neurodegeneration. Frontiers In Neuroendocrinology,33(1):105-115.
11Vegeto, E, Benedusi, V, Maggi, A (2008) Estrogen anti-inflammatory activity inbrain: A therapeutic opportunity for menopause and neurodegenerative diseases.Frontiers In Neuroendocrinology,29(4):507-519.
12Polazzi, E, Monti, B (2010) Microglia and neuroprotection: from in vitro studies totherapeutic applications. Progress In Neurobiology,92(3):293-315.
13Arevalo, M, Santos-Galindo, M, Bellini, M, Azcoitia, I, Garcia-Segura, LM (2010)Actions of estrogens on glial cells: Implications for neuroprotection. Biochimica etBiophysica Acta (BBA)-General Subjects,1800(10):1106-1112.
14McEwen BS, Alves SE（1999）Estrogen actions in the central nervous system. EndocrRev20:279–307
15Stout Steele, M, Bennett, RA (2011) Clinical Technique: Dorsal Ovariectomy inRodents. Journal of Exotic Pet Medicine,20(3):222-226.
16de Chaves, G, Moretti, M, Castro, AA, Dagostin, W, Da, SG, Boeck, CR, Quevedo, J,Gavioli, EC (2009) Effects of long-term ovariectomy on anxiety and behavioral despairin rats. Physiology&Behavior,97(3-4):420-425.17Smith, JA, Das, A, Ray, SK, Banik, NL (2012) Role of pro-inflammatory cytokinesreleased from microglia in neurodegenerative diseases. Brain Research Bulletin,87(1):10-20.
18Lee, C, Landreth, G (2010) The role of microglia in amyloid clearance from the ADbrain. Journal of Neural Transmission,117(8):949.
19Lue, L, Kuo, Y, Beach, T, Walker, D (2010) Microglia Activation andAnti-inflammatory Regulation in Alzheimer’s Disease. Molecular Neurobiology,41(2):115.
20Pan, X, Zhu, Y, Lin, N, Zhang, J, Ye, Q, Huang, H, Chen, X (2011) Microglialphagocytosis induced by fibrillar β-amyloid is attenuated by oligomeric β-amyloid:implications for Alzheimer's disease. Molecular Neurodegeneration,6(1):1.
21Lei, DL, Long, JM, Hengemihle, J, O'Neill, J, Manaye, KF, Ingram, DK, Mouton, PR(2003) Effects of estrogen and raloxifene on neuroglia number and morphology in thehippocampus of aged female mice. Neuroscience,121(3):659-666.
22LeBlanc ES, Janowsky J, Chan BK, Nelson HD (2011) Hormone replacement therapyand cognition: systematic review and meta analysis. JAMA285:1489-99
23Espeland MA, etal.(2004) Conjugated equine estrogens and global cognitivefunction in postmenopausal women: Women's Health Initiative Memory Study. JAMA.291:2959-68
24Shumar SA, et al.(2004) Conjugated equine estrogens and incidence of probabledementia and mild cognitive impairment in postmenopausal women: Women’s HealthInitiative Memory Study. JAMA291:2947-58
25Turgeon JL, Carr MC, Maki PM, Mendelsohn ME, Wise PM.(2006) Complex actionsof sex steroids in adipose tissue, the cardiovascular system, and brain: Insights frombasic science and clinical studies. Endocr Rev.27(6):575-605.
26Doncarlos LL, Azcoitia I, Garcia-Segura LM（2009）Neuroprotective actions ofselective estrogen receptor modulators Psychoneuroendocrinology.34S1:S113-S122.
27Kulak Júnior J, Kulak CA, Taylor HS.（2010）SERMs in the prevention andtreatment of postmenopausal osteoporosis: an update. Arq Bras Endocrinol Metabol.54(2):200-5.
28Silverman SL.（2010）New selective estrogen receptor modulators (SERMs) indevelopment. Curr Osteoporos Rep.8(3):151-3.
29Nilsson S, Gustafsson J.（2011） Estrogen receptors: therapies targeted toreceptor subtypes. Clin Pharmacol Ther.89(1):44-55.
30Bruce-Keller, AJ, Keeling, JL, Keller, JN, Huang, FF, Camondola, S, Mattson, MP(2000) Antiinflammatory effects of estrogen on microglial activation. Endocrinology,141(10):3646-3656.
31Vegeto, E, Belcredito, S, Etteri, S, Ghisletti, S, Brusadelli, A, Meda, C, Krust, A,Dupont, S, Ciana, P, Chambon, P, Maggi, A (2003) Estrogen receptor-alpha mediatesthe brain antiinflammatory activity of estradiol. Proc Natl Acad Sci U S A,100(16):9614-9619.
32Elzer, JG, Muhammad, S, Wintermantel, TM, Regnier-Vigouroux, A, Ludwig, J, Schutz,G, Schwaninger, M (2010) Neuronal estrogen receptor-alpha mediates neuroprotectionby17beta-estradiol. J Cereb Blood Flow Metab,30(5):935-942.
33Liu, X, Fan, XL, Zhao, Y, Luo, GR, Li, XP, Li, R, Le WD (2005) Estrogen providesneuroprotection against activated microglia-induced dopaminergic neuronal injurythrough both estrogen receptor-alpha and estrogen receptor-beta in microglia.Journal Of Neuroscience Research,81(5):653-665.
34Baker, AE, Brautigam, VM, Watters, JJ (2004) Estrogen modulates microglialinflammatory mediator production via interactions with estrogen receptor beta.Endocrinology,145(11):5021-5032.
35Wood, H (2011) Neuroimmunology: estrogen receptor ligands suppressinflammatory responses in astrocytes and microglia. Nat Rev Neurol,7(7):355.
Acconcia, F, Kumar, R (2006) Signaling regulation of genomic and nongenomic functionsof estrogen receptors. Cancer Letters238(1):1-14.
Carroll, JC, Pike, CJ (2008) Selective estrogen receptor modulators differentially regulateAlzheimer-like changes in female3xTg-AD mice. Endocrinology149(5):2607-2611.
Espeland, MA, Rapp, SR, Shumaker, SA, Brunner, R, et al.(2004) Conjugated equineestrogens and global cognitive function in postmenopausal women: Women's HealthInitiative Memory Study. JAMA291(24):2959-2968.
Foster, TC (2011) Role of estrogen receptor alpha and beta expression and signaling oncognitive function during aging. Hippocampus,.
Frye, CA, Duffy, CK, Walf, AA (2007) Estrogens and progestins enhance spatial learningof intact and ovariectomized rats in the object placement task. Neurobiology Of LearningAnd Memory88(2):208-216.
Grisouard, J, Medunjanin, S, Hermani, A, Shukla, A, et al.(2007) Glycogen synthasekinase-3protects estrogen receptor alpha from proteasomal degradation and is required forfull transcriptional activity of the receptor. Molecular Endocrinology21(10):2427-2439.
Harris, HA, Katzenellenbogen, JA, Katzenellenbogen, BS (2002) Characterization ofthe biological roles of the estrogen receptors, ERalpha and ERbeta, in estrogen targettissues in vivo through the use of an ERalpha-selective ligand. Endocrinology143(11):4172-4177.
Lewis, DK, Johnson, AB, Stohlgren, S, Harms, A, et al.(2008) Effects of estrogenreceptor agonists on regulation of the inflammatory response in astrocytes from young adultand middle-aged female rats. Journal Of Neuroimmunology195(1-2):47-59.
Li, C, Brake, WG, Romeo, RD, Dunlop, JC, et al.(2004) Estrogen alters hippocampaldendritic spine shape and enhances synaptic protein immunoreactivity and spatial memoryin female mice. Proc Natl Acad Sci U S A101(7):2185-2190.
Li, J, Siegel, M, Yuan, M, Zeng, Z, et al.(2011) Estrogen enhances neurogenesis andbehavioral recovery after stroke. J Cereb Blood Flow Metab31(2):413-425.
Liu, F, Day, M, Muniz, LC, Bitran, D, et al.(2008) Activation of estrogen receptor-betaregulates hippocampal synaptic plasticity and improves memory. Nature Neuroscience,11(3):334-343.
McEwen, B, Akama, K, Alves, S, Brake, WG, et al.(2001) Tracking the estrogenreceptor in neurons: implications for estrogen-induced synapse formation. Proc Natl AcadSci U S A,98(13):7093-7100.
McEwen, BS, Alves, SE (1999) Estrogen actions in the central nervous system. EndocrineReviews,20(3):279-307.
Morissette, M, Le Saux, M, D Astous, M, Jourdain, et al.(2008) Contribution ofestrogen receptors alpha and beta to the effects of estradiol in the brain. The Journal ofSteroid Biochemistry and Molecular Biology108(3-5):327-338.
Morissette, M, Le Saux, M, Di Paolo, T (2008) Effect of oestrogen receptor alpha andbeta agonists on brain N-methyl-D-aspartate receptors. Journal Of Neuroendocrinology,20(8):1006-1014.
Morrison, JH (2011) A mechanism emerges for the critical period hypothesis for estrogentreatment. Proc Natl Acad Sci U S A,108(35):14375-14376.
Mukai, H, Kimoto, T, Hojo, Y, Kawato, S, et al.(2010) Modulation of synaptic plasticityby brain estrogen in the hippocampus. Biochim Biophys Acta1800(10):1030-1044.
Okamoto, K, Sekiguchi, M (1991) Synaptic receptors and intracellular signal transductionin the cerebellum. Neuroscience Research9(4):213-236.
O'Neill, EE, Blewett, AR, Loria, PM, Greene, GL (2008) Modulation of alphaCaMKIIsignaling by rapid ERalpha action. Brain Research1222:1-17.
Savonenko, AV, Markowska, AL (2003) The cognitive effects of ovariectomy andestrogen replacement are modulated by aging. Neuroscience119(3):821-830.
Sherwin, BB (2009) Estrogen therapy: is time of initiation critical for neuroprotection? NatRev Endocrinol5(11):620-627.
Shumaker, SA, Legault, C, Kuller, L, Rapp, SR, et al.(2004) Conjugated equineestrogens and incidence of probable dementia and mild cognitive impairment inpostmenopausal women: Women's Health Initiative Memory Study. JAMA291(24):2947-2958.
Smith, CC, McMahon, LL (2005) Estrogen-induced increase in the magnitude oflong-term potentiation occurs only when the ratio of NMDA transmission to AMPAtransmission is increased. Journal Of Neuroscience,25(34):7780-7791.
Srivastava, DP, Woolfrey, KM, Liu, F, Brandon, NJ, et al.(2010) Estrogen receptor ssactivity modulates synaptic signaling and structure. Journal of Neuroscience30(40):13454-13460.
Suzuki, S, Brown, CM, Dela, CC, Yang, E, et al.(2007) Timing of estrogen therapy afterovariectomy dictates the efficacy of its neuroprotective and antiinflammatory actions. ProcNatl Acad Sci U S A104(14):6013-6018.
Tiwari-Woodruff, S, Morales, LB, Lee, R, Voskuhl, RR (2007) Differentialneuroprotective and antiinflammatory effects of estrogen receptor (ER)alpha and ERbetaligand treatment. Proc Natl Acad Sci U S A104(37):14813-14818.
Vegeto, E, Belcredito, S, Etteri, S, Ghisletti, S, et al.(2003) Estrogen receptor-alphamediates the brain antiinflammatory activity of estradiol. Proc Natl Acad Sci U S A,100(16):9614-9619.
Vegeto, E, Belcredito, S, Ghisletti, S, Meda, C, et al.(2006) The endogenous estrogenstatus regulates microglia reactivity in animal models of neuroinflammation. Endocrinology147(5):2263-2272.
Waters, EM, Mitterling, K, Spencer, JL, Mazid, S, et al.(2009) Estrogen receptor alphaand beta specific agonists regulate expression of synaptic proteins in rat hippocampus.Brain Research1290:1-11.
Zhang, QG, Han, D, Wang, RM, Dong, Y, et al.(2011) C terminus of Hsc70-interactingprotein (CHIP)-mediated degradation of hippocampal estrogen receptor-alpha and thecritical period hypothesis of estrogen neuroprotection. Proc Natl Acad Sci U S A108(35):E617-E624.
Zhang, QG, Raz, L, Wang, R, Han, D, et al.(2009) Estrogen attenuates ischemic oxidativedamage via an estrogen receptor alpha-mediated inhibition of NADPH oxidase activation.Journal of Neuroscience29(44):13823-13836.
Andersen, K, Launer, LJ, Dewey, ME, Letenneur, L, et al.(1999) Gender differences inthe incidence of AD and vascular dementia: The EURODEM Studies. EURODEMIncidence Research Group. Neurology,53(9):1992-1997.
Bethea, CL, Smith, AW, Centeno, ML, Reddy, AP (2011) Long-term ovariectomydecreases serotonin neuron number and gene expression in free ranging macaques.Neuroscience192:675-688.
Bonomo, SM, Rigamonti, AE, Giunta, M, Galimberti, D, et al.(2009) Menopausaltransition: a possible risk factor for brain pathologic events. Neurobiology of Aging30(1):71-80.
Brinton, R D (2005) Investigative models for determining hormone therapy-inducedoutcomes in brain: evidence in support of a healthy cell bias of estrogen action. Annals ofthe New York Academy of Sciences.1052,57-74.
Carroll, JC, Pike, CJ (2008) Selective estrogen receptor modulators differentially regulateAlzheimer-like changes in female3xTg-AD mice. Endocrinology149(5):2607-2611.
Choleris, E, Gustafsson, JA, Korach, KS, Muglia, LJ, et al.(2003) Anestrogen-dependent four-gene micronet regulating social recognition: a study with oxytocinand estrogen receptor-alpha and-beta knockout mice. Proceedings of the National Academyof Sciences USA100(10):6192-6197.
Choleris, E, Kavaliers, M, Pfaff, DW (2004) Functional genomics of social recognition.Journal of Neuroendocrinology16(4):383-389.
Choleris, E, Ogawa, S, Kavaliers, M, Gustafsson, JA, et al.(2006) Involvement ofestrogen receptor alpha, beta and oxytocin in social discrimination: A detailed behavioralanalysis with knockout female mice. Genes Brain and Behavior5(7):528-539.
Cordey, M, Pike, CJ (2005) Neuroprotective properties of selective estrogen receptoragonists in cultured neurons. Brain Research1045(1-2):217-223.
Correia, SC, Santos, RX, Cardoso, S, Carvalho, C, et al.(2010) Effects of estrogen inthe brain: is it a neuroprotective agent in Alzheimer's disease? Current Aging Science3(2):113-126.
Dubal, DB, Zhu, H, Yu, J, Rau, SW, et al.(2001) Estrogen receptor alpha, not beta, is acritical link in estradiol-mediated protection against brain injury. Proceedings of theNational Academy of Sciences USA41483198.
Daniel, JM, Bohacek, J (2010) The critical period hypothesis of estrogen effects oncognition: Insights from basic research. Biochim Biophys Acta1800(10):1068-1076.
Espeland, MA, Rapp, SR, Shumaker, SA, Brunner, R, et al.(2004) Conjugated equineestrogens and global cognitive function in postmenopausal women: Women's HealthInitiative Memory Study. JAMA291(24):2959-2968.
Foster, TC (2012) Role of estrogen receptor alpha and beta expression and signaling oncognitive function during aging. Hippocampus22(4):656-69.
Frye, CA, Duffy, CK, Walf, AA (2007) Estrogens and progestins enhance spatial learningof intact and ovariectomized rats in the object placement task. Neurobiology of Learningand Memory88(2):208-216.
Gleason, C E,Cholerton, B, Carlsson, C M, Johnson, S C, et al.(2005) Neuroprotective effects of female sex steroids in humans: current controversies and futuredirections. Cellular and Molecular Life Sciences.62,299-312.
Gordon, A, Aguilar, R, Garrido-Gracia, JC, Guil-Luna, S, et al.(2009) Activation ofestrogen receptor-alpha induces gonadotroph progesterone receptor expression and actiondifferently in young and middle-aged ovariectomized rats. Human Reproduction,24(10):2618-2628.
Le Saux, M, Estrada-Camarena, E, Di Paolo, T (2006) Selective estrogen receptor-alphabut not-beta agonist treatment modulates brainalpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. Journal ofNeuroscience Research84(5):1076-1084.
LeBlanc, ES, Janowsky, J, Chan, BK, Nelson, HD (2001) Hormone replacement therapyand cognition: systematic review and meta-analysis. JAMA285(11):1489-1499.
Lewis, DK, Johnson, AB, Stohlgren, S, Harms, A, et al.(2008) Effects of estrogenreceptor agonists on regulation of the inflammatory response in astrocytes from young adultand middle-aged female rats. Journal of Neuroimmunology195(1-2):47-59.
Li, C, Brake, WG, Romeo, RD, Dunlop, JC, et al.(2004) Estrogen alters hippocampaldendritic spine shape and enhances synaptic protein immunoreactivity and spatial memoryin female mice. Proceedings of the National Academy of Sciences USA101(7):2185-2190.
Li, J, Siegel, M, Yuan, M, Zeng, Z, et al.(2011) Estrogen enhances neurogenesis andbehavioral recovery after stroke. Journal of Cerebral Blood Flow Metabolism31(2):413-425.
Liu, F, Day, M, Muniz, LC, Bitran, D, et al.(2008) Activation of estrogen receptor-betaregulates hippocampal synaptic plasticity and improves memory. Nature Neuroscience,11(3):334-343.
McEwen, BS, Alves, SE (1999) Estrogen actions in the central nervous system. EndocrineReviews20(3):279-307.
McEwen, B, Akama, K, Alves, S, Brake, WG, et al.(2001) Tracking the estrogen receptorin neurons: implications for estrogen-induced synapse formation. Proceedings of theNational Academy of Sciences U S A,98(13):7093-7100.
McEwen, B (2002) Estrogen actions throughout the brain. Recent Progress in HormoneResearch.57,357-384.
Mitra, SW, Hoskin, E, Yudkovitz, J, Pear, L, et al.(2003) Immunolocalization ofestrogen receptor beta in the mouse brain: comparison with estrogen receptor alpha.Endocrinology144(5):2055-2067.
Moult, P R,Harvey,J (2008) Hormonal regulation of hippocampal dendritic morphologyand synaptic plasticity. Cell adhesion&migration4,269-275.
Moriarty, K, Kim, KH, Bender, JR (2006) Minireview: estrogen receptor-mediated rapidsignaling. Endocrinology147(12):5557-5563.
Morissette, M, Le Saux, M, D Astous, M, Jourdain, S, et al.(2008a) Contribution ofestrogen receptors alpha and beta to the effects of estradiol in the brain. The Journal ofSteroid Biochemistry and Molecular Biology108(3-5):327-338.
Morissette, M, Le Saux, M, Di Paolo, T (2008b) Effect of oestrogen receptor alpha andbeta agonists on brain N-methyl-D-aspartate receptors. Journal of Neuroendocrinology20(8):1006-1014.
Morrison, JH (2011) A mechanism emerges for the critical period hypothesis for estrogentreatment. Proceedings of the National Academy of Sciences USA108(35):14375-14376.
Mukai, H, Kimoto, T, Hojo, Y, Kawato, S, et al.(2010) Modulation of synaptic plasticityby brain estrogen in the hippocampus. Biochimica et Biophysica Acta1800(10):1030-1044.
O'Neill, EE, Blewett, AR, Loria, PM, Greene, GL (2008) Modulation of alphaCaMKIIsignaling by rapid ERalpha action. Brain Research1222:1-17.
Pike, CJ, Carroll, JC, Rosario, ER, Barron, AM (2009) Protective actions of sex steroidhormones in Alzheimer's disease. Frontiers in Neuroendocrinology30(2):239-258.
Pompili, A, Arnone, B, Gasbarri, A (2012) Estrogens and memory in physiological andneuropathological conditions. Psychoneuroendocrinology.(Epub ahead of print)
Rissman, EF, Heck, AL, Leonard, JE, Shupnik, MA, et al.(2002) Disruption of estrogenreceptor beta gene impairs spatial learning in female mice. Proceedings of the NationalAcademy of Sciences USA99(6):3996-4001.
Rocca, WA, Bower, JH, Maraganore, DM, Ahlskog, JE, et al.(2007) Increased risk ofcognitive impairment or dementia in women who underwent oophorectomy beforemenopause. Neurology69(11):1074-1083.
Rocca, WA, Grossardt, BR, Shuster, LT (2010) Oophorectomy, menopause, estrogen, andcognitive aging: the timing hypothesis. Neurodegenerative Diseases7(1-3):163-166.
Ramon-Molinier, E.(1970) The Golgi-Cox technique, In: Nauta WJH., Ebbesson SOE.(Eds.)―Contemporary research methods in neuroanatomy‖pp:106-131. Springer, NY.
Sawai, T, Bernier, F, Fukushima, T, Hashimoto, T, et al.(2002) Estrogen induces a rapidincrease of calcium-calmodulin-dependent protein kinase II activity in the hippocampus.Brain Research,950(1-2):308-311.
Sherwin, BB, Henry, J F (2008) Brain aging modulates the neuroprotective effects ofestrogen on selective aspects of cognition in women: A critical review. Frontiers inNeuroendocrinology.29,88-113.
Sherwin, BB (2009) Estrogen therapy: is time of initiation critical for neuroprotection?Nature Review Endocrinology5(11):620-627.
Shughrue, PJ, Lane, MV, Merchenthaler, I (1997) Comparative distribution of estrogenreceptor-alpha and-beta mRNA in the rat central nervous system. Journal of ComparativeNeurology388(4):507-525.
Shumaker, SA, Legault, C, Kuller, L, Rapp, SR, et al.(2004) Conjugated equineestrogens and incidence of probable dementia and mild cognitive impairment inpostmenopausal women: Women's Health Initiative Memory Study. JAMA291(24):2947-2958.
Shuster, LT, Gostout, BS, Grossardt, BR, Rocca, WA (2008) Prophylactic oophorectomyin premenopausal women and long-term health. Menopause International14(3):111-116.
Simpkins, JW, Perez, E, Xiaofei Wang, ShaoHua Yang, et al.(2009) Review: Thepotential for estrogens in preventing Alzheimer's disease and vascular dementia.Therapeutic Advances in Neurological Disorders2(1):31-49.
Smith, CC, McMahon, LL (2005) Estrogen-induced increase in the magnitude oflong-term potentiation occurs only when the ratio of NMDA transmission to AMPAtransmission is increased. Journal of Neuroscience25(34):7780-7791.
Smith, CC, Vedder, LC, Nelson, AR, Bredemann, TM, et al.(2010) Duration of estrogendeprivation, not chronological age, prevents estrogen's ability to enhance hippocampalsynaptic physiology. Proceedings of the National Academy of Sciences USA107(45):19543-19548.
Stout Steele, M, Bennett, RA (2011) Clinical Technique: Dorsal Ovariectomy in Rodents.Journal of Exotic Pet Medicine20(3):222-226.
Suzuki, S, Brown, CM, Dela, CC, Yang, E, et al.(2007) Timing of estrogen therapy afterovariectomy dictates the efficacy of its neuroprotective and antiinflammatory actions.Proceedings of the National Academy of Sciences USA104(14):6013-6018.
Thakur, MK, Sharma, PK (2006) Aging of brain: role of estrogen. NeurochemicalResearch31(11):1389-1398.
Srivastava, DP, Woolfrey, KM, Liu, F, Brandon, NJ, Penzes, P (2010) Estrogenreceptor ss activity modulates synaptic signaling and structure. Journal of Neuroscience,30(40):13454-13460.
Thakur, MK, Sharma, PK (2006) Aging of brain: role of estrogen. NeurochemicalResearch31(11):1389-1398.
Tiwari-Woodruff, S, Morales, LB, Lee, R, Voskuhl, RR (2007) Differentialneuroprotective and antiinflammatory effects of estrogen receptor (ER)alpha and ERbetaligand treatment. Proceedings of the National Academy of Sciences USA104(37):14813-14818.
Turgeon, JL, Carr, MC, Maki, PM, Mendelsohn, ME, et al.(2006) Complex actions ofsex steroids in adipose tissue, the cardiovascular system, and brain: Insights from basicscience and clinical studies. Endocrine Reviews,27(6):575-605.
Vegeto, E, Belcredito, S, Etteri, S, Ghisletti, S, Brusadelli, A, et al.(2003) Estrogenreceptor-alpha mediates the brain antiinflammatory activity of estradiol. Proceedings of theNational Academy of Sciences USA100(16):9614-9619.
Vegeto, E, Belcredito, S, Ghisletti, S, Meda, C, et al.(2006) The endogenous estrogenstatus regulates microglia reactivity in animal models of neuroinflammation. Endocrinology147(5):2263-2272.
Walf, AA, Paris, JJ, Rhodes, ME, Simpkins, JW, et al.(2011) Divergent mechanisms fortrophic actions of estrogens in the brain and peripheral tissues. Brain Research1379:119-136.
Waters, EM, Mitterling, K, Spencer, JL, Mazid, S, et al.(2009) Estrogen receptor alphaand beta specific agonists regulate expression of synaptic proteins in rat hippocampus.Brain Research1290:1-11.
Wang, L, Andersson, S, Warner, M, Gustafsson, JA (2003) Estrogen receptor (ER)betaknockout mice reveal a role for ERbeta in migration of cortical neurons in the developingbrain. Proceedings of the National Academy of Sciences USA,100(2):703-708.
Woolley, C S, Gould, E,Frankfurt, M, McEwen, B S (1990) Naturally occurringfuctuation in dendritic spine density on adult hippocampal pyramidal neurons. Journal ofNeuroscience10,4035-4039.
Woolley, C S (2007) Acute effects of estrogen on neuronal physiology. Annual Review ofPharmacology and Toxicology47,657-680.
Yang, LC, Zhang, QG, Zhou, CF, Yang, F, et al.(2010) Extranuclear estrogen receptorsmediate the neuroprotective effects of estrogen in the rat hippocampus. PLoS One5(5):e9851.
Yildirim, M, Janssen, WG, Lou, WY, Akama, KT, et al.(2011) Effects of estrogen andaging on the synaptic distribution of phosphorylated Akt-immunoreactivity in the CA1region of the female rat hippocampus. Brain Research,1379:98-108.
Zandi, PP, Carlson, MC, Plassman, BL, Welsh-Bohmer, KA, et al.(2002) Hormonereplacement therapy and incidence of Alzheimer disease in older women: the Cache CountyStudy. JAMA288(17):2123-2129.
Zhang, QG, Han, D, Wang, RM, Dong, Y, et al.(2011) C terminus of Hsc70-interactingprotein (CHIP)-mediated degradation of hippocampal estrogen receptor-alpha and thecritical period hypothesis of estrogen neuroprotection. Proceedings of the NationalAcademy of Sciences USA108(35): E617-E624.
Zhang, QG, Raz, L, Wang, R, Han, D, et al.(2009) Estrogen attenuates ischemicoxidative damage via an estrogen receptor alpha-mediated inhibition of NADPH oxidaseactivation. Journal of Neuroscience29(44):13823-13836.
Zhao, L, Yao, J, Mao, Z, Chen, S, et al.(2011)17β-Estradiol regulates insulin-degradingenzyme expression via an ERβ/PI3-K pathway in hippocampus: Relevance to Alzheimer'sprevention. Neurobiology of Aging32(11):1949-1963.
1. Ali A, Hoeflich KP, Woodgett JR.(2001) Glycogen Synthase Kinase-3: Properties,Functions, and Regulation Chemical Reviews101,8
2.Carol A Grimes, Richard S Jope (2001)The multifaceted roles of glycogen synthasekinase3in cellular signaling Progress in Neurobiology65,391–426
3. Goodenough S, Schleusner D, Pietrzik C, Skutella T, et al.(2005) Glycogen synthasekinase3β links neuroprotection by17β-estradiol to key Alzheimer processes Neuroscience132,581–589
4. Fe′lix Herna′ndez, Jesu′s Avila (2008) The role of glycogen synthase kinase3in theearly stages ofAlzheimers’disease FEBS Letters582,3848–3854
5. Hernández F, de Barreda EG, Fuster-Matanzo A, Go i-Oliver P, et al.(2009) Therole of GSK3in Alzheimer disease Brain Research Bulletin80,248–250
6. Hernández F, Gómez de Barreda E, Fuster-Matanzo A, Lucas JJ, et al.(2010) GSK3:A possible link between beta amyloid peptide and tau protein Experimental Neurology223(2):322-5.
7. Akihiko Takashima (2009) Drug Development Targeting the Glycogen SynthaseKinase-3β (GSK-3β)-Mediated Signal Transduction Pathway:Role of GSK-3β in AdultBrain Journal of Pharmacological Sciences109,174-178
8. Y. Balaramana, A. R. Limayea, A.I.Leveyb, S. Srinivasana (2006) Glycogen synthasekinase3and Alzheimer’s disease: pathophysiological and therapeutic significanceCellular and Molecular Life Sciences63,1226–1235
9.Zandi, PP, Carlson, MC, Plassman, BL, Welsh-Bohmer, KA, et al.(2002) Hormonereplacement therapy and incidence of Alzheimer disease in older women: the Cache CountyStudy. JAMA288(17):2123-2129.
10. Jean Grisouard, Doris Mayer (2009) Specifc involvement of glycogen synthasekinase-3in the function and activity of sex steroid hormone receptors reveals thecomplexity of their regulation Journal of Steroid Biochemistry&Molecular Biology117,87–92
11. Jean Grisouard, Senad Medunjanin, Alexander Hermani, Ashish Shukla, et al.(2005) Glycogen Synthase Kinase-3Protects Estrogen Receptor from ProteasomalDegradation and Is Required for Full Transcriptional Activity of the Receptor MolecularEndocrinology21(10):2427–2439
12. Senad Medunjanin, Alexander Hermani, Barbara De Servi, Jean Grisouard, et al.(2005) Glycogen Synthase Kinase-3Interacts with and Phosphorylates Estrogen Receptorand Is Involved in the Regulation of Receptor Activity The Journal of BiologicalChemistry3006–33014
13. Beaulieu, J.M., Gainetdinov, R.R., Caron, M.G (2007) The Akt-GSK-3signalingcascade in the actions of dopamine Trends in Pharmacological Sciences28,166—172.
14. Alimohamad, H., Rajakumar, N., Seah, YH, Rushlow W.(2005) Antipsychotics alterthe protein expression levels of beta-catenin and GSK-3in the rat medial prefrontal cortexand striatum Biological Psychiatry57,533-542.
15. Cardona-Gomez, P, Perez M. Avila, J., Garcia-Segura, L.M., Wandosell, F (2004)Estradiol inhibits GSK3and regulates interaction of estrogen receptors GSK3, and beta-catenin in the hippocampus Molecular and Cellular Neuroscience25,363-373.
16. Shumaker, SA, Legault, C, Kuller, L, Rapp, SR, et al.(2004) Conjugated equineestrogens and incidence of probable dementia and mild cognitive impairment inpostmenopausal women: Women's Health Initiative Memory Study. JAMA291(24):2947-2958.
17.Shuster, LT, Gostout, BS, Grossardt, BR, Rocca, WA (2008) Prophylacticoophorectomy in premenopausal women and long-term health. Menopause International14(3):111-116.
18. Simpkins, JW, Perez, E, Xiaofei Wang, ShaoHua Yang, et al.(2009) Review: Thepotential for estrogens in preventing Alzheimer's disease and vascular dementia.Therapeutic Advances in Neurological Disorders2(1):31-49.
19.Morissette, M, Le Saux, M, Di Paolo, T (2008b) Effect of oestrogen receptor alphaand beta agonists on brain N-methyl-D-aspartate receptors. Journal of Neuroendocrinology20(8):1006-1014.
20. Morrison, JH (2011) A mechanism emerges for the critical period hypothesis forestrogen treatment. Proceedings of the National Academy of Sciences USA108(35):14375-14376.
21. Mukai, H, Kimoto, T, Hojo, Y, Kawato, S, et al.(2010) Modulation of synapticplasticity by brain estrogen in the hippocampus. Biochim Biophys Acta1800(10):1030-1044.
1Walf AA, Paris JJ, Rhodes ME, Simpkins JW, Frye CA (2011) Divergent mechanismsfor trophic actions of estrogens in the brain and peripheral tissues. Brain Resarch16:1379:119-36.
2Li J, Siegel M, Yuan M, Zeng Z, Finnucan L, Persky R, Hurn PD, McCullough LD (2011)Estrogen enhances neurogenesis and behavioral recovery after stroke. Journal ofCerebral Blood Flow&Metabolism31(2):413-25.
3Suzuki S, Brown CM, Dela Cruz CD, Yang E, Bridwell DA, Wise PM (2007) Timingof estrogen therapy after ovariectomy dictates the efficacy of its neuroprotective and antiinflammatory actions. Proc. Natl Acad. Sci. USA3:104(14):6013-8
4Correia SC, Santos RX, Cardoso S, Carvalho C, Santos MS, Oliveira CR, Moreira PI（2010）Effects of Estrogen in the Brain: Is it a Neuroprotective Agent in Alzheimer’sDisease? Current Aging Science3:113-126
5Walter A. Rocca, Brandon R. Grossardt, Lynne T. Shuster（2010）Oophorectomy,Meno-pause, Estrogen, and Cognitive Aging: The Timing Hypothesis Neuro-degenerative Dis7:163–166
6Zhang, QG, Han, D, Wang, RM, Dong, Y, Yang, F, Vadlamudi, RK, Brann, DW (2011)C terminus of Hsc70-interacting protein (CHIP)-mediated degradation ofhippocampal estrogen receptor-alpha and the critical period hypothesis of estrogenneuroprotection. Proc. Natl Acad. Sci. USA108(35): E617-E624.
7Zhang, QG, Raz, L, Wang, R, Han, D, De Sevilla, L, Yang, F, Vadlamudi, RK, Brann,DW (2009) Estrogen attenuates ischemic oxidative damage via an estrogen receptoralpha-mediated inhibition of NADPH oxidase activation. Journal of Neuroscience,29(44):13823-13836.
8Andjelkovic, AV, Pachter, JS (1998) Central nervous system endothelium in neuro-inflammatory, neuroinfectious, and neurodegenerative disease. Journal ofNeuroscience Research,51(4):423-430.
9Floyd, RA (1999) Neuroinflammatory processes are important in neurodegenerativediseases: an hypothesis to explain the increased formation of reactive oxygen andnitrogen species as major factors involved in neurodegenerative disease development.Free Radic Biol Med,26(9-10):1346-1355.
10Spence, RD, Voskuhl, RR (2012) Neuroprotective effects of estrogens and androgensin CNS inflammation and neurodegeneration. Frontiers In Neuroendocrinology,33(1):105-115.
11Vegeto, E, Benedusi, V, Maggi, A (2008) Estrogen anti-inflammatory activity inbrain: A therapeutic opportunity for menopause and neurodegenerative diseases.Frontiers In Neuroendocrinology,29(4):507-519.
12Polazzi, E, Monti, B (2010) Microglia and neuroprotection: from in vitro studies totherapeutic applications. Progress In Neurobiology,92(3):293-315.
13Arevalo, M, Santos-Galindo, M, Bellini, M, Azcoitia, I, Garcia-Segura, LM (2010)Actions of estrogens on glial cells: Implications for neuroprotection. Biochimica etBiophysica Acta (BBA)-General Subjects,1800(10):1106-1112.
14McEwen BS, Alves SE（1999）Estrogen actions in the central nervous system. EndocrRev20:279–307
15Stout Steele, M, Bennett, RA (2011) Clinical Technique: Dorsal Ovariectomy inRodents. Journal of Exotic Pet Medicine,20(3):222-226.
16de Chaves, G, Moretti, M, Castro, AA, Dagostin, W, Da, SG, Boeck, CR, Quevedo, J,Gavioli, EC (2009) Effects of long-term ovariectomy on anxiety and behavioral despairin rats. Physiology&Behavior,97(3-4):420-425.17Smith, JA, Das, A, Ray, SK, Banik, NL (2012) Role of pro-inflammatory cytokinesreleased from microglia in neurodegenerative diseases. Brain Research Bulletin,87(1):10-20.
18Lee, C, Landreth, G (2010) The role of microglia in amyloid clearance from the ADbrain. Journal of Neural Transmission,117(8):949.
19Lue, L, Kuo, Y, Beach, T, Walker, D (2010) Microglia Activation andAnti-inflammatory Regulation in Alzheimer’s Disease. Molecular Neurobiology,41(2):115.
20Pan, X, Zhu, Y, Lin, N, Zhang, J, Ye, Q, Huang, H, Chen, X (2011) Microglialphagocytosis induced by fibrillar β-amyloid is attenuated by oligomeric β-amyloid:implications for Alzheimer's disease. Molecular Neurodegeneration,6(1):1.
21Lei, DL, Long, JM, Hengemihle, J, O'Neill, J, Manaye, KF, Ingram, DK, Mouton, PR(2003) Effects of estrogen and raloxifene on neuroglia number and morphology in thehippocampus of aged female mice. Neuroscience,121(3):659-666.
22LeBlanc ES, Janowsky J, Chan BK, Nelson HD (2011) Hormone replacement therapyand cognition: systematic review and meta analysis. JAMA285:1489-99
23Espeland MA, etal.(2004) Conjugated equine estrogens and global cognitivefunction in postmenopausal women: Women's Health Initiative Memory Study. JAMA.291:2959-68
24Shumar SA, et al.(2004) Conjugated equine estrogens and incidence of probabledementia and mild cognitive impairment in postmenopausal women: Women’s HealthInitiative Memory Study. JAMA291:2947-58
25Turgeon JL, Carr MC, Maki PM, Mendelsohn ME, Wise PM.(2006) Complex actionsof sex steroids in adipose tissue, the cardiovascular system, and brain: Insights frombasic science and clinical studies. Endocr Rev.27(6):575-605.
26Doncarlos LL, Azcoitia I, Garcia-Segura LM（2009）Neuroprotective actions ofselective estrogen receptor modulators Psychoneuroendocrinology.34S1:S113-S122.
27Kulak Júnior J, Kulak CA, Taylor HS.（2010）SERMs in the prevention andtreatment of postmenopausal osteoporosis: an update. Arq Bras Endocrinol Metabol.54(2):200-5.
28Silverman SL.（2010）New selective estrogen receptor modulators (SERMs) indevelopment. Curr Osteoporos Rep.8(3):151-3.
29Nilsson S, Gustafsson J.（2011） Estrogen receptors: therapies targeted toreceptor subtypes. Clin Pharmacol Ther.89(1):44-55.
30Bruce-Keller, AJ, Keeling, JL, Keller, JN, Huang, FF, Camondola, S, Mattson, MP(2000) Antiinflammatory effects of estrogen on microglial activation. Endocrinology,141(10):3646-3656.
31Vegeto, E, Belcredito, S, Etteri, S, Ghisletti, S, Brusadelli, A, Meda, C, Krust, A,Dupont, S, Ciana, P, Chambon, P, Maggi, A (2003) Estrogen receptor-alpha mediatesthe brain antiinflammatory activity of estradiol. Proc Natl Acad Sci U S A,100(16):9614-9619.
32Elzer, JG, Muhammad, S, Wintermantel, TM, Regnier-Vigouroux, A, Ludwig, J, Schutz,G, Schwaninger, M (2010) Neuronal estrogen receptor-alpha mediates neuroprotectionby17beta-estradiol. J Cereb Blood Flow Metab,30(5):935-942.
33Liu, X, Fan, XL, Zhao, Y, Luo, GR, Li, XP, Li, R, Le WD (2005) Estrogen providesneuroprotection against activated microglia-induced dopaminergic neuronal injurythrough both estrogen receptor-alpha and estrogen receptor-beta in microglia.Journal Of Neuroscience Research,81(5):653-665.
34Baker, AE, Brautigam, VM, Watters, JJ (2004) Estrogen modulates microglialinflammatory mediator production via interactions with estrogen receptor beta.Endocrinology,145(11):5021-5032.
35Wood, H (2011) Neuroimmunology: estrogen receptor ligands suppressinflammatory responses in astrocytes and microglia. Nat Rev Neurol,7(7):355.
Acconcia, F, Kumar, R (2006) Signaling regulation of genomic and nongenomic functionsof estrogen receptors. Cancer Letters238(1):1-14.
Carroll, JC, Pike, CJ (2008) Selective estrogen receptor modulators differentially regulateAlzheimer-like changes in female3xTg-AD mice. Endocrinology149(5):2607-2611.
Espeland, MA, Rapp, SR, Shumaker, SA, Brunner, R, et al.(2004) Conjugated equineestrogens and global cognitive function in postmenopausal women: Women's HealthInitiative Memory Study. JAMA291(24):2959-2968.
Foster, TC (2011) Role of estrogen receptor alpha and beta expression and signaling oncognitive function during aging. Hippocampus,.
Frye, CA, Duffy, CK, Walf, AA (2007) Estrogens and progestins enhance spatial learningof intact and ovariectomized rats in the object placement task. Neurobiology Of LearningAnd Memory88(2):208-216.
Grisouard, J, Medunjanin, S, Hermani, A, Shukla, A, et al.(2007) Glycogen synthasekinase-3protects estrogen receptor alpha from proteasomal degradation and is required forfull transcriptional activity of the receptor. Molecular Endocrinology21(10):2427-2439.
Harris, HA, Katzenellenbogen, JA, Katzenellenbogen, BS (2002) Characterization ofthe biological roles of the estrogen receptors, ERalpha and ERbeta, in estrogen targettissues in vivo through the use of an ERalpha-selective ligand. Endocrinology143(11):4172-4177.
Lewis, DK, Johnson, AB, Stohlgren, S, Harms, A, et al.(2008) Effects of estrogenreceptor agonists on regulation of the inflammatory response in astrocytes from young adultand middle-aged female rats. Journal Of Neuroimmunology195(1-2):47-59.
Li, C, Brake, WG, Romeo, RD, Dunlop, JC, et al.(2004) Estrogen alters hippocampaldendritic spine shape and enhances synaptic protein immunoreactivity and spatial memoryin female mice. Proc Natl Acad Sci U S A101(7):2185-2190.
Li, J, Siegel, M, Yuan, M, Zeng, Z, et al.(2011) Estrogen enhances neurogenesis andbehavioral recovery after stroke. J Cereb Blood Flow Metab31(2):413-425.
Liu, F, Day, M, Muniz, LC, Bitran, D, et al.(2008) Activation of estrogen receptor-betaregulates hippocampal synaptic plasticity and improves memory. Nature Neuroscience,11(3):334-343.
McEwen, B, Akama, K, Alves, S, Brake, WG, et al.(2001) Tracking the estrogenreceptor in neurons: implications for estrogen-induced synapse formation. Proc Natl AcadSci U S A,98(13):7093-7100.
McEwen, BS, Alves, SE (1999) Estrogen actions in the central nervous system. EndocrineReviews,20(3):279-307.
Morissette, M, Le Saux, M, D Astous, M, Jourdain, et al.(2008) Contribution ofestrogen receptors alpha and beta to the effects of estradiol in the brain. The Journal ofSteroid Biochemistry and Molecular Biology108(3-5):327-338.
Morissette, M, Le Saux, M, Di Paolo, T (2008) Effect of oestrogen receptor alpha andbeta agonists on brain N-methyl-D-aspartate receptors. Journal Of Neuroendocrinology,20(8):1006-1014.
Morrison, JH (2011) A mechanism emerges for the critical period hypothesis for estrogentreatment. Proc Natl Acad Sci U S A,108(35):14375-14376.
Mukai, H, Kimoto, T, Hojo, Y, Kawato, S, et al.(2010) Modulation of synaptic plasticityby brain estrogen in the hippocampus. Biochim Biophys Acta1800(10):1030-1044.
Okamoto, K, Sekiguchi, M (1991) Synaptic receptors and intracellular signal transductionin the cerebellum. Neuroscience Research9(4):213-236.
O'Neill, EE, Blewett, AR, Loria, PM, Greene, GL (2008) Modulation of alphaCaMKIIsignaling by rapid ERalpha action. Brain Research1222:1-17.
Savonenko, AV, Markowska, AL (2003) The cognitive effects of ovariectomy andestrogen replacement are modulated by aging. Neuroscience119(3):821-830.
Sherwin, BB (2009) Estrogen therapy: is time of initiation critical for neuroprotection? NatRev Endocrinol5(11):620-627.
Shumaker, SA, Legault, C, Kuller, L, Rapp, SR, et al.(2004) Conjugated equineestrogens and incidence of probable dementia and mild cognitive impairment inpostmenopausal women: Women's Health Initiative Memory Study. JAMA291(24):2947-2958.
Smith, CC, McMahon, LL (2005) Estrogen-induced increase in the magnitude oflong-term potentiation occurs only when the ratio of NMDA transmission to AMPAtransmission is increased. Journal Of Neuroscience,25(34):7780-7791.
Srivastava, DP, Woolfrey, KM, Liu, F, Brandon, NJ, et al.(2010) Estrogen receptor ssactivity modulates synaptic signaling and structure. Journal of Neuroscience30(40):13454-13460.
Suzuki, S, Brown, CM, Dela, CC, Yang, E, et al.(2007) Timing of estrogen therapy afterovariectomy dictates the efficacy of its neuroprotective and antiinflammatory actions. ProcNatl Acad Sci U S A104(14):6013-6018.
Tiwari-Woodruff, S, Morales, LB, Lee, R, Voskuhl, RR (2007) Differentialneuroprotective and antiinflammatory effects of estrogen receptor (ER)alpha and ERbetaligand treatment. Proc Natl Acad Sci U S A104(37):14813-14818.
Vegeto, E, Belcredito, S, Etteri, S, Ghisletti, S, et al.(2003) Estrogen receptor-alphamediates the brain antiinflammatory activity of estradiol. Proc Natl Acad Sci U S A,100(16):9614-9619.
Vegeto, E, Belcredito, S, Ghisletti, S, Meda, C, et al.(2006) The endogenous estrogenstatus regulates microglia reactivity in animal models of neuroinflammation. Endocrinology147(5):2263-2272.
Waters, EM, Mitterling, K, Spencer, JL, Mazid, S, et al.(2009) Estrogen receptor alphaand beta specific agonists regulate expression of synaptic proteins in rat hippocampus.Brain Research1290:1-11.
Zhang, QG, Han, D, Wang, RM, Dong, Y, et al.(2011) C terminus of Hsc70-interactingprotein (CHIP)-mediated degradation of hippocampal estrogen receptor-alpha and thecritical period hypothesis of estrogen neuroprotection. Proc Natl Acad Sci U S A108(35):E617-E624.
Zhang, QG, Raz, L, Wang, R, Han, D, et al.(2009) Estrogen attenuates ischemic oxidativedamage via an estrogen receptor alpha-mediated inhibition of NADPH oxidase activation.Journal of Neuroscience29(44):13823-13836.