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ISSN (Online): 1996-3181

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Mini-Review Article

Epigenetic Modifications by Estrogen and Androgen in Alzheimer’s Disease

Author(s): Rajnish Kumar*, Faiza Fatima, Garima Yadav, Simran Singh, Subhagata Haldar, Athanasios Alexiou and Ghulam Md Ashraf

Volume 22, Issue 1, 2023

Published on: 30 March, 2022

Page: [6 - 17] Pages: 12

DOI: 10.2174/1871527321666220225110501

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Abstract

For the development and maintenance of neuron networks in the brain, epigenetic mechanisms are necessary, as indicated by recent findings. This includes some of the high-order brain processes, such as behavior and cognitive functions. Epigenetic mechanisms could influence the pathophysiology or etiology of some neuronal diseases, altering disease susceptibility and therapy responses. Recent studies support epigenetic dysfunctions in neurodegenerative and psychiatric conditions, such as Alzheimer's disease (AD). These dysfunctions in epigenetic mechanisms also play crucial roles in the transgenerational effects of the environment on the brain and subsequently in the inheritance of pathologies. The possible role of gonadal steroids in the etiology and progression of neurodegenerative diseases, including Alzheimer’s disease, has become the subject of a growing body of research over the last 20 years. Recent scientific findings suggest that epigenetic changes, driven by estrogen and androgens, play a vital role in brain functioning. Therefore, exploring the role of estrogen and androgen-based epigenetic changes in the brain is critical for the deeper understanding of AD. This review highlights the epigenetic modifications caused by these two gonadal steroids and the possible therapeutic strategies for AD.

Keywords: Alzheimer's disease, androgen, brain, epigenetic modifications, estrogen, neuronal diseases.

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[1]
Miller CA, Campbell SL, Sweatt JD. DNA methylation and histone acetylation work in concert to regulate memory formation and synaptic plasticity. Neurobiol Learn Mem 2008; 89(4): 599-603.
[http://dx.doi.org/10.1016/j.nlm.2007.07.016] [PMID: 17881251]
[2]
Martini L, Melcangi RC, Maggi R. Androgen and progesterone metabolism in the central and peripheral nervous system. J Steroid Biochem Mol Biol 1993; 47(1-6): 195-205.
[http://dx.doi.org/10.1016/0960-0760(93)90075-8] [PMID: 8274436]
[3]
Zwain IH, Yen SS, Cheng CY. Astrocytes cultured in vitro produce estradiol-17beta and express aromatase cytochrome P-450 (P-450 AROM) mRNA. Biochim Biophys Acta 1997; 1334(2-3): 338-48.
[http://dx.doi.org/10.1016/S0304-4165(96)00115-8] [PMID: 9101730]
[4]
Pak TR, Chung WC, Lund TD, Hinds LR, Clay CM, Handa RJ. The androgen metabolite, 5alpha-androstane-3beta, 17beta-diol, is a potent modulator of estrogen receptor-beta1-mediated gene transcription in neuronal cells. Endocrinology 2005; 146(1): 147-55.
[http://dx.doi.org/10.1210/en.2004-0871] [PMID: 15471969]
[5]
MacLusky NJ, Hajszan T, Prange-Kiel J, Leranth C. Androgen modulation of hippocampal synaptic plasticity. Neuroscience 2006; 138(3): 957-65.
[http://dx.doi.org/10.1016/j.neuroscience.2005.12.054] [PMID: 16488544]
[6]
Janowsky JS. The role of androgens in cognition and brain aging in men. Neuroscience 2006; 138(3): 1015-20.
[http://dx.doi.org/10.1016/j.neuroscience.2005.09.007] [PMID: 16310318]
[7]
Patchev VK, Schroeder J, Goetz F, Rohde W, Patchev AV. Neurotropic action of androgens: Principles, mechanisms and novel targets. Exp Gerontol 2004; 39(11-12): 1651-60.
[http://dx.doi.org/10.1016/j.exger.2004.07.011] [PMID: 15582281]
[8]
Wimer CC, Wimer RE. On the sources of strain and sex differences in granule cell number in the dentate area of house mice. Brain Res Dev Brain Res 1989; 48(2): 167-76.
[http://dx.doi.org/10.1016/0165-3806(89)90073-4] [PMID: 2776294]
[9]
Roof RL. The dentate gyrus is sexually dimorphic in prepubescent rats: Testosterone plays a significant role. Brain Res 1993; 610(1): 148-51.
[http://dx.doi.org/10.1016/0006-8993(93)91228-K] [PMID: 8518922]
[10]
Cruz G, Foster W, Paredes A, Yi KD, Uzumcu M. Long-term effects of early-life exposure to environmental oestrogens on ovarian function: Role of epigenetics. J Neuroendocrinol 2014; 26(9): 613-24.
[http://dx.doi.org/10.1111/jne.12181] [PMID: 25040227]
[11]
Wilkinson HN, Hardman MJ. The role of estrogen in cutaneous ageing and repair. Maturitas 2017; 103: 60-4.
[http://dx.doi.org/10.1016/j.maturitas.2017.06.026] [PMID: 28778334]
[12]
Frick KM, Zhao Z, Fan L. The epigenetics of estrogen: Epigenetic regulation of hormone-induced memory enhancement. Epigenetics 2011; 6(6): 675-80.
[http://dx.doi.org/10.4161/epi.6.6.16177] [PMID: 21593594]
[13]
Woolley CS. Acute effects of estrogen on neuronal physiology. Annu Rev Pharmacol Toxicol 2007; 47(1): 657-80.
[http://dx.doi.org/10.1146/annurev.pharmtox.47.120505.105219] [PMID: 16918306]
[14]
Hamilton KJ, Hewitt SC, Arao Y, Korach KS. Estrogen hormone biology. Curr Top Dev Biol 2017; 125: 109-46.
[http://dx.doi.org/10.1016/bs.ctdb.2016.12.005] [PMID: 28527569]
[15]
Gustafsson JA, Strom A, Warner M. Update on ERbeta. J Steroid Biochem Mol Biol 2019; 191: 105312.
[http://dx.doi.org/10.1016/j.jsbmb.2019.02.007] [PMID: 30995525]
[16]
Warner M, Huang B, Gustafsson JA. Estrogen receptor β as a pharmaceutical target. Trends Pharmacol Sci 2017; 38(1): 92-9.
[http://dx.doi.org/10.1016/j.tips.2016.10.006] [PMID: 27979317]
[17]
Abrahám IM, Todman MG, Korach KS, Herbison AE. Critical in vivo roles for classical estrogen receptors in rapid estrogen actions on intracellular signaling in mouse brain. Endocrinology 2004; 145(7): 3055-61.
[http://dx.doi.org/10.1210/en.2003-1676] [PMID: 14976146]
[18]
Tsugawa Y, Hiramoto M, Imai T. Estrogen induces estrogen receptor α expression and hepatocyte proliferation in late pregnancy. Biochem Biophys Res Commun 2019; 511(3): 592-6.
[http://dx.doi.org/10.1016/j.bbrc.2019.02.119] [PMID: 30826053]
[19]
Zhao Z, Fan L, Frick KM. Epigenetic alterations regulate estradiol-induced enhancement of memory consolidation. Proc Natl Acad Sci USA 2010; 107(12): 5605-10.
[http://dx.doi.org/10.1073/pnas.0910578107] [PMID: 20212170]
[20]
Eichenbaum H. Declarative memory: Insights from cognitive neurobiology. Annu Rev Psychol 1997; 48(1): 547-72.
[http://dx.doi.org/10.1146/annurev.psych.48.1.547] [PMID: 9046568]
[21]
Squire LR. Memory and the hippocampus: A synthesis from findings with rats, monkeys, and humans. Psychol Rev 1992; 99(2): 195-231.
[http://dx.doi.org/10.1037/0033-295X.99.2.195] [PMID: 1594723]
[22]
Mayeux R, Stern Y. Epidemiology of Alzheimer disease. Cold Spring Harb Perspect Med 2012; 2(8): a006239.
[http://dx.doi.org/10.1101/cshperspect.a006239] [PMID: 22908189]
[23]
Chouraki V, Seshadri S. Genetics of Alzheimer’s disease. Adv Genet 2014; 87: 245-94.
[http://dx.doi.org/10.1016/B978-0-12-800149-3.00005-6] [PMID: 25311924]
[24]
Ertekin-Taner N. Genetics of Alzheimer’s disease: A centennial review. Neurol Clin 2007; 25(3): 611-67.
[http://dx.doi.org/10.1016/j.ncl.2007.03.009] [PMID: 17659183]
[25]
Kivipelto M, Mangialasche F. Alzheimer disease: To what extent can Alzheimer disease be prevented? Nat Rev Neurol 2014; 10(10): 552-3.
[http://dx.doi.org/10.1038/nrneurol.2014.170] [PMID: 25245154]
[26]
Chouliaras L, van den Hove DL, Kenis G, et al. Prevention of age-related changes in hippocampal levels of 5-methylcytidine by caloric restriction. Neurobiol Aging 2012; 33(8): 1672-81.
[http://dx.doi.org/10.1016/j.neurobiolaging.2011.06.003] [PMID: 21764481]
[27]
Chouliaras L, van den Hove DL, Kenis G, et al. Histone deacetylase 2 in the mouse hippocampus: Attenuation of age-related increase by caloric restriction. Curr Alzheimer Res 2013; 10(8): 868-76.
[http://dx.doi.org/10.2174/1567205011310080009] [PMID: 24093534]
[28]
Heyn H, Li N, Ferreira HJ, et al. Distinct DNA methylomes of newborns and centenarians. Proc Natl Acad Sci USA 2012; 109(26): 10522-7.
[http://dx.doi.org/10.1073/pnas.1120658109] [PMID: 22689993]
[29]
Nugent BM, Schwarz JM, McCarthy MM. Hormonally mediated epigenetic changes to steroid receptors in the developing brain: Implications for sexual differentiation. Horm Behav 2011; 59(3): 338-44.
[http://dx.doi.org/10.1016/j.yhbeh.2010.08.009] [PMID: 20800064]
[30]
Pike CJ. Sex and the development of Alzheimer’s disease. J Neurosci Res 2017; 95(1-2): 671-80.
[http://dx.doi.org/10.1002/jnr.23827] [PMID: 27870425]
[31]
Pellegrini C, Pirazzini C, Sala C, et al. A meta-analysis of brain DNA methylation across sex, age, and Alzheimer’s disease points for accelerated epigenetic aging in neurodegeneration. Front Aging Neurosci 2021; 13: 639428.
[http://dx.doi.org/10.3389/fnagi.2021.639428] [PMID: 33790779]
[32]
Haettig J, Stefanko DP, Multani ML, Figueroa DX, McQuown SC, Wood MA. HDAC inhibition modulates hippocampus-dependent long-term memory for object location in a CBP-dependent manner. Learn Mem 2011; 18(2): 71-9.
[http://dx.doi.org/10.1101/lm.1986911] [PMID: 21224411]
[33]
Kilgore M, Miller CA, Fass DM, et al. Inhibitors of class 1 histone deacetylases reverse contextual memory deficits in a mouse model of Alzheimer’s disease. Neuropsychopharmacology 2010; 35(4): 870-80.
[http://dx.doi.org/10.1038/npp.2009.197] [PMID: 20010553]
[34]
Ricobaraza A, Cuadrado-Tejedor M, Pérez-Mediavilla A, Frechilla D, Del Río J, García-Osta A. Phenylbutyrate ameliorates cognitive deficit and reduces tau pathology in an Alzheimer’s disease mouse model. Neuropsychopharmacology 2009; 34(7): 1721-32.
[http://dx.doi.org/10.1038/npp.2008.229] [PMID: 19145227]
[35]
Végh MJ, Heldring CM, Kamphuis W, et al. Reducing hippocampal extracellular matrix reverses early memory deficits in a mouse model of Alzheimer’s disease. Acta Neuropathol Commun 2014; 2(1): 76.
[http://dx.doi.org/10.1186/s40478-014-0076-z] [PMID: 24974208]
[36]
Bao XQ, Li N, Wang T, et al. FLZ alleviates the memory deficits in transgenic mouse model of Alzheimer’s disease via decreasing beta-amyloid production and tau hyperphosphorylation. PLoS One 2013; 8(11): e78033.
[http://dx.doi.org/10.1371/journal.pone.0078033] [PMID: 24223757]
[37]
Wang G, Jiang X, Pu H, et al. Scriptaid, a novel histone deacetylase inhibitor, protects against traumatic brain injury via modulation of PTEN and AKT pathway: Scriptaid protects against TBI via AKT. Neurotherapeutics 2013; 10(1): 124-42.
[http://dx.doi.org/10.1007/s13311-012-0157-2] [PMID: 23132328]
[38]
Oliveira AM, Wood MA, McDonough CB, Abel T. Transgenic mice expressing an inhibitory truncated form of p300 exhibit long-term memory deficits. Learn Mem 2007; 14(9): 564-72.
[http://dx.doi.org/10.1101/lm.656907] [PMID: 17761541]
[39]
Maurice T, Duclot F, Meunier J, et al. Altered memory capacities and response to stress in p300/CBP-associated factor (PCAF) histone acetylase knockout mice. Neuropsychopharmacology 2008; 33(7): 1584-602.
[http://dx.doi.org/10.1038/sj.npp.1301551] [PMID: 17805310]
[40]
Duclot F, Jacquet C, Gongora C, Maurice T. Alteration of working memory but not in anxiety or stress response in p300/CBP associated factor (PCAF) histone acetylase knockout mice bred on a C57BL/6 background. Neurosci Lett 2010; 475(3): 179-83.
[http://dx.doi.org/10.1016/j.neulet.2010.03.077] [PMID: 20371377]
[41]
Alarcón JM, Malleret G, Touzani K, et al. Chromatin acetylation, memory, and LTP are impaired in CBP+/- mice: A model for the cognitive deficit in Rubinstein-Taybi syndrome and its amelioration. Neuron 2004; 42(6): 947-59.
[http://dx.doi.org/10.1016/j.neuron.2004.05.021] [PMID: 15207239]
[42]
Wood MA, Kaplan MP, Park A, et al. Transgenic mice expressing a truncated form of CREB-Binding Protein (CBP) exhibit deficits in hippocampal synaptic plasticity and memory storage. Learn Mem 2005; 12(2): 111-9.
[http://dx.doi.org/10.1101/lm.86605] [PMID: 15805310]
[43]
Chwang WB, O’Riordan KJ, Levenson JM, Sweatt JD. ERK/MAPK regulates hippocampal histone phosphorylation following contextual fear conditioning. Learn Mem 2006; 13(3): 322-8.
[http://dx.doi.org/10.1101/lm.152906] [PMID: 16741283]
[44]
Adams JP, Sweatt JD. Molecular psychology: Roles for the ERK MAP kinase cascade in memory. Annu Rev Pharmacol Toxicol 2002; 42(1): 135-63.
[http://dx.doi.org/10.1146/annurev.pharmtox.42.082701.145401] [PMID: 11807168]
[45]
Selvi BR, Cassel JC, Kundu TK, Boutillier AL. Tuning acetylation levels with HAT activators: Therapeutic strategy in neurodegenerative diseases. Biochim Biophys Acta 2010; 1799(10-12): 840-53.
[http://dx.doi.org/10.1016/j.bbagrm.2010.08.012] [PMID: 20833281]
[46]
Miller CA, Sweatt JD. Covalent modification of DNA regulates memory formation. Neuron 2007; 53(6): 857-69.
[http://dx.doi.org/10.1016/j.neuron.2007.02.022] [PMID: 17359920]
[47]
Levenson JM, Roth TL, Lubin FD, et al. Evidence that DNA (cytosine-5) methyltransferase regulates synaptic plasticity in the hippocampus. J Biol Chem 2006; 281(23): 15763-73.
[http://dx.doi.org/10.1074/jbc.M511767200] [PMID: 16606618]
[48]
Sunthamala N, Sankla N, Chuerduangphui J, et al. Enhancement of specific T-lymphocyte responses by monocyte-derived dendritic cells pulsed with E2 protein of human papillomavirus 16 and human p16INK4A. PeerJ 2020; 8: e9213.
[http://dx.doi.org/10.7717/peerj.9213] [PMID: 32509466]
[49]
Hojo Y, Hattori TA, Enami T, et al. Adult male rat hippocampus synthesizes estradiol from pregnenolone by cytochromes P45017alpha and P450 aromatase localized in neurons. Proc Natl Acad Sci USA 2004; 101(3): 865-70.
[http://dx.doi.org/10.1073/pnas.2630225100] [PMID: 14694190]
[50]
Kretz O, Fester L, Wehrenberg U, et al. Hippocampal synapses depend on hippocampal estrogen synthesis. J Neurosci 2004; 24(26): 5913-21.
[http://dx.doi.org/10.1523/JNEUROSCI.5186-03.2004] [PMID: 15229239]
[51]
Daniel JM. Effects of oestrogen on cognition: What have we learned from basic research? J Neuroendocrinol 2006; 18(10): 787-95.
[http://dx.doi.org/10.1111/j.1365-2826.2006.01471.x] [PMID: 16965297]
[52]
Luine VN, Jacome LF, Maclusky NJ. Rapid enhancement of visual and place memory by estrogens in rats. Endocrinology 2003; 144(7): 2836-44.
[http://dx.doi.org/10.1210/en.2003-0004] [PMID: 12810538]
[53]
Gresack JE, Frick KM. Post-training estrogen enhances spatial and object memory consolidation in female mice. Pharmacol Biochem Behav 2006; 84(1): 112-9.
[http://dx.doi.org/10.1016/j.pbb.2006.04.013] [PMID: 16759685]
[54]
Blanco JC, Minucci S, Lu J, et al. The histone acetylase PCAF is a nuclear receptor coactivator. Genes Dev 1998; 12(11): 1638-51.
[http://dx.doi.org/10.1101/gad.12.11.1638] [PMID: 9620851]
[55]
Kishimoto M, Fujiki R, Takezawa S, et al. Nuclear receptor mediated gene regulation through chromatin remodeling and histone modifications. Endocr J 2006; 53(2): 157-72.
[http://dx.doi.org/10.1507/endocrj.53.157] [PMID: 16618973]
[56]
Spencer JL, Waters EM, Romeo RD, Wood GE, Milner TA, McEwen BS. Uncovering the mechanisms of estrogen effects on hippocampal function. Front Neuroendocrinol 2008; 29(2): 219-37.
[http://dx.doi.org/10.1016/j.yfrne.2007.08.006] [PMID: 18078984]
[57]
Tanapat P, Hastings NB, Reeves AJ, Gould E. Estrogen stimulates a transient increase in the number of new neurons in the dentate gyrus of the adult female rat. J Neurosci 1999; 19(14): 5792-801.
[http://dx.doi.org/10.1523/JNEUROSCI.19-14-05792.1999] [PMID: 10407020]
[58]
Spencer JL, Waters EM, Milner TA, McEwen BS. Estrous cycle regulates activation of hippocampal Akt, LIM kinase, and neurotrophin receptors in C57BL/6 mice. Neuroscience 2008; 155(4): 1106-19.
[http://dx.doi.org/10.1016/j.neuroscience.2008.05.049] [PMID: 18601981]
[59]
Vaucher E, Reymond I, Najaffe R, et al. Estrogen effects on object memory and cholinergic receptors in young and old female mice. Neurobiol Aging 2002; 23(1): 87-95.
[http://dx.doi.org/10.1016/S0197-4580(01)00250-0] [PMID: 11755023]
[60]
Frye CA, Duffy CK, Walf AA. Estrogens and progestins enhance spatial learning of intact and ovariectomized rats in the object placement task. Neurobiol Learn Mem 2007; 88(2): 208-16.
[http://dx.doi.org/10.1016/j.nlm.2007.04.003] [PMID: 17507257]
[61]
Fernandez SM, Lewis MC, Pechenino AS, et al. Estradiol-induced enhancement of object memory consolidation involves hippocampal extracellular signal-regulated kinase activation and membrane-bound estrogen receptors. J Neurosci 2008; 28(35): 8660-7.
[http://dx.doi.org/10.1523/JNEUROSCI.1968-08.2008] [PMID: 18753366]
[62]
Fan L, Zhao Z, Orr PT, Chambers CH, Lewis MC, Frick KM. Estradiol-induced object memory consolidation in middle-aged female mice requires dorsal hippocampal extracellular signal-regulated kinase and phosphatidylinositol 3-kinase activation. J Neurosci 2010; 30(12): 4390-400.
[http://dx.doi.org/10.1523/JNEUROSCI.4333-09.2010] [PMID: 20335475]
[63]
Patel S, Homaei A, Raju AB, Meher BR. Estrogen: The necessary evil for human health, and ways to tame it. Biomed Pharmacother 2018; 102: 403-11.
[http://dx.doi.org/10.1016/j.biopha.2018.03.078] [PMID: 29573619]
[64]
Kumar R, Zakharov MN, Khan SH, et al. The dynamic structure of the estrogen receptor. J Amino Acids 2011; 2011: 812540.
[http://dx.doi.org/10.4061/2011/812540] [PMID: 22312471]
[65]
Hornung MW, Tapper MA, Denny JS, et al. Effects-based chemical category approach for prioritization of low affinity estrogenic chemicals. SAR QSAR Environ Res 2014; 25(4): 289-323.
[http://dx.doi.org/10.1080/1062936X.2014.898692] [PMID: 24779616]
[66]
Zhao C, Dahlman-Wright K, Gustafsson JA. Estrogen receptor beta: An overview and update. Nucl Recept Signal 2008; 6(1): e003.
[http://dx.doi.org/10.1621/nrs.06003] [PMID: 18301783]
[67]
Poola I. Molecular assays to profile 10 estrogen receptor beta isoform mRNA copy numbers in ovary, breast, uterus, and bone tissues. Endocrine 2003; 22(2): 101-12.
[http://dx.doi.org/10.1385/ENDO:22:2:101] [PMID: 14665713]
[68]
Kim EK, Choi EJ. Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta 2010; 1802(4): 396-405.
[http://dx.doi.org/10.1016/j.bbadis.2009.12.009] [PMID: 20079433]
[69]
Verhulst PJ, Depoortere I. Ghrelin’s second life: From appetite stimulator to glucose regulator. World J Gastroenterol 2012; 18(25): 3183-95.
[http://dx.doi.org/10.3748/wjg.v18.i25.3183] [PMID: 22783041]
[70]
Cersosimo MG, Benarroch EE. Estrogen actions in the nervous system: Complexity and clinical implications. Neurology 2015; 85(3): 263-73.
[http://dx.doi.org/10.1212/WNL.0000000000001776] [PMID: 26109716]
[71]
Macedo-Garzón B, Loredo-Ranjel R, Chávez-Maldonado M, Jiménez-Flores JR, Villamar-Duque TE, Cárdenas R. Distribution and expression of GnRH 1, kiss receptor 2, and estradiol α and ß receptors in the anterior brain of females of Chirostoma humboldtianum. Fish Physiol Biochem 2021; 47(1): 33-47.
[http://dx.doi.org/10.1007/s10695-020-00891-9] [PMID: 33118089]
[72]
Mahboobifard F, Dargahi L, Jorjani M, Ramezani Tehrani F, Pourgholami MH. The role of ERα36 in cell type-specific functions of estrogen and cancer development. Pharmacol Res 2021; 163: 105307.
[http://dx.doi.org/10.1016/j.phrs.2020.105307] [PMID: 33246174]
[73]
Toran-Allerand CD. Estrogen and the brain: Beyond ER-alpha, ER-beta, and 17beta-estradiol. Ann N Y Acad Sci 2005; 1052(1): 136-44.
[http://dx.doi.org/10.1196/annals.1347.009] [PMID: 16024756]
[74]
Contreras-Zárate MJ, Day NL, Ormond DR, et al. Estradiol induces BDNF/TrkB signaling in triple-negative breast cancer to promote brain metastases. Oncogene 2019; 38(24): 4685-99.
[http://dx.doi.org/10.1038/s41388-019-0756-z] [PMID: 30796353]
[75]
Boulware MI, Weick JP, Becklund BR, Kuo SP, Groth RD, Mermelstein PG. Estradiol activates group I and II metabotropic glutamate receptor signaling, leading to opposing influences on cAMP response element-binding protein. J Neurosci 2005; 25(20): 5066-78.
[http://dx.doi.org/10.1523/JNEUROSCI.1427-05.2005] [PMID: 15901789]
[76]
Bourtchuladze R, Frenguelli B, Blendy J, Cioffi D, Schutz G, Silva AJ. Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein. Cell 1994; 79(1): 59-68.
[http://dx.doi.org/10.1016/0092-8674(94)90400-6] [PMID: 7923378]
[77]
Rouaux C, Loeffler JP, Boutillier AL. Targeting CREB-binding protein (CBP) loss of function as a therapeutic strategy in neurological disorders. Biochem Pharmacol 2004; 68(6): 1157-64.
[http://dx.doi.org/10.1016/j.bcp.2004.05.035] [PMID: 15313413]
[78]
Vargas KG, Milic J, Zaciragic A, et al. The functions of estrogen receptor beta in the female brain: A systematic review. Maturitas 2016; 93: 41-57.
[http://dx.doi.org/10.1016/j.maturitas.2016.05.014] [PMID: 27338976]
[79]
Merlo S, Spampinato SF, Sortino MA. Estrogen and Alzheimer’s disease: Still an attractive topic despite disappointment from early clinical results. Eur J Pharmacol 2017; 817: 51-8.
[http://dx.doi.org/10.1016/j.ejphar.2017.05.059] [PMID: 28577965]
[80]
Klinge CM, Clark BJ, Prough RA. Dehydroepiandrosterone research: Past, current, and future. Vitam Horm 2018; 108: 1-28.
[http://dx.doi.org/10.1016/bs.vh.2018.02.002] [PMID: 30029723]
[81]
Zhao L, Yao J, Mao Z, Chen S, Wang Y, Brinton RD. 17β-Estradiol regulates insulin-degrading enzyme expression via an ERβ/PI3-K pathway in hippocampus: Relevance to Alzheimer’s prevention. Neurobiol Aging 2011; 32(11): 1949-63.
[http://dx.doi.org/10.1016/j.neurobiolaging.2009.12.010] [PMID: 20053478]
[82]
Waters EM, Mitterling K, Spencer JL, Mazid S, McEwen BS, Milner TA. Estrogen receptor alpha and beta specific agonists regulate expression of synaptic proteins in rat hippocampus. Brain Res 2009; 1290: 1-11.
[http://dx.doi.org/10.1016/j.brainres.2009.06.090] [PMID: 19596275]
[83]
Andersen K, Launer LJ, Dewey ME, et al. Gender differences in the incidence of AD and vascular dementia: The EURODEM Studies. Neurology 1999; 53(9): 1992-7.
[http://dx.doi.org/10.1212/WNL.53.9.1992] [PMID: 10599770]
[84]
Perfilova VN, Tyurenkov IN. [Glutamate metabotropic receptors: Structure, localisation, functions] Usp Fiziol Nauk 2016; 47(2): 98-112.
[PMID: 27530046]
[85]
Liu F, Day M, Muñiz LC, et al. Activation of estrogen receptor-beta regulates hippocampal synaptic plasticity and improves memory. Nat Neurosci 2008; 11(3): 334-43.
[http://dx.doi.org/10.1038/nn2057] [PMID: 18297067]
[86]
Niswender CM, Conn PJ. Metabotropic glutamate receptors: Physiology, pharmacology, and disease. Annu Rev Pharmacol Toxicol 2010; 50(1): 295-322.
[http://dx.doi.org/10.1146/annurev.pharmtox.011008.145533] [PMID: 20055706]
[87]
Jones KJ, Brown TJ, Damaser M. Neuroprotective effects of gonadal steroids on regenerating peripheral motoneurons. Brain Res Brain Res Rev 2001; 37(1-3): 372-82.
[http://dx.doi.org/10.1016/S0165-0173(01)00107-2] [PMID: 11744101]
[88]
Jones KJ, Coers S, Storer PD, Tanzer L, Kinderman NB. Androgenic regulation of the central glia response following nerve damage. J Neurobiol 1999; 40(4): 560-73.
[http://dx.doi.org/10.1002/(SICI)1097-4695(19990915)40:4<560:AID-NEU11>3.0.CO;2-I] [PMID: 10453056]
[89]
Pike CJ, Nguyen TV, Ramsden M, Yao M, Murphy MP, Rosario ER. Androgen cell signaling pathways involved in neuroprotective actions. Horm Behav 2008; 53(5): 693-705.
[http://dx.doi.org/10.1016/j.yhbeh.2007.11.006] [PMID: 18222446]
[90]
Beyenburg S, Watzka M, Clusmann H, et al. Androgen receptor mRNA expression in the human hippocampus. Neurosci Lett 2000; 294(1): 25-8.
[http://dx.doi.org/10.1016/S0304-3940(00)01542-1] [PMID: 11044578]
[91]
Kerr JE, Allore RJ, Beck SG, Handa RJ. Distribution and hormonal regulation of Androgen Receptor (AR) and AR messenger ribonucleic acid in the rat hippocampus. Endocrinology 1995; 136(8): 3213-21.
[http://dx.doi.org/10.1210/endo.136.8.7628354] [PMID: 7628354]
[92]
Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: Progress and problems on the road to therapeutics. Science 2002; 297(5580): 353-6.
[http://dx.doi.org/10.1126/science.1072994] [PMID: 12130773]
[93]
Kaufman JM, Vermeulen A. The decline of androgen levels in elderly men and its clinical and therapeutic implications. Endocr Rev 2005; 26(6): 833-76.
[http://dx.doi.org/10.1210/er.2004-0013] [PMID: 15901667]
[94]
Hogervorst E, Williams J, Budge M, Barnetson L, Combrinck M, Smith AD. Serum total testosterone is lower in men with Alzheimer’s disease. Neuroendocrinol Lett 2001; 22(3): 163-8.
[PMID: 11449190]
[95]
Hogervorst E, Lehmann DJ, Warden DR, McBroom J, Smith AD. Apolipoprotein E epsilon4 and testosterone interact in the risk of Alzheimer’s disease in men. Int J Geriatr Psychiatry 2002; 17(10): 938-40.
[http://dx.doi.org/10.1002/gps.714] [PMID: 12325053]
[96]
Hogervorst E, Combrinck M, Smith AD. Testosterone and gonadotropin levels in men with dementia Neuroendocrinol Lett 2003; 24(3-4): 203-8.
[PMID: 14523358]
[97]
Cortes CJ, Ling SC, Guo LT, et al. Muscle expression of mutant androgen receptor accounts for systemic and motor neuron disease phenotypes in spinal and bulbar muscular atrophy. Neuron 2014; 82(2): 295-307.
[http://dx.doi.org/10.1016/j.neuron.2014.03.001] [PMID: 24742458]
[98]
Sopher BL, Thomas PS Jr, LaFevre-Bernt MA, et al. Androgen receptor YAC transgenic mice recapitulate SBMA motor neuronopathy and implicate VEGF164 in the motor neuron degeneration. Neuron 2004; 41(5): 687-99.
[http://dx.doi.org/10.1016/S0896-6273(04)00082-0] [PMID: 15003169]
[99]
Tohgi H, Utsugisawa K, Yamagata M, Yoshimura M. Effects of age on messenger RNA expression of glucocorticoid, thyroid hormone, androgen, and estrogen receptors in postmortem human hippocampus. Brain Res 1995; 700(1-2): 245-53.
[http://dx.doi.org/10.1016/0006-8993(95)00971-R] [PMID: 8624717]
[100]
Li S, Jin M, Koeglsperger T, Shepardson NE, Shankar GM, Selkoe DJ. Soluble Aβ oligomers inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NR2B-containing NMDA receptors. J Neurosci 2011; 31(18): 6627-38.
[http://dx.doi.org/10.1523/JNEUROSCI.0203-11.2011] [PMID: 21543591]
[101]
Palop JJ, Mucke L. Amyloid-beta-induced neuronal dysfunction in Alzheimer’s disease: From synapses toward neural networks. Nat Neurosci 2010; 13(7): 812-8.
[http://dx.doi.org/10.1038/nn.2583] [PMID: 20581818]
[102]
Talantova M, Sanz-Blasco S, Zhang X, et al. Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss. Proc Natl Acad Sci USA 2013; 110(27): E2518-27.
[http://dx.doi.org/10.1073/pnas.1306832110] [PMID: 23776240]
[103]
Meitzen J, Mermelstein PG. Estrogen receptors stimulate brain region specific metabotropic glutamate receptors to rapidly initiate signal transduction pathways. J Chem Neuroanat 2011; 42(4): 236-41.
[http://dx.doi.org/10.1016/j.jchemneu.2011.02.002] [PMID: 21458561]
[104]
Lee E, Sidoryk-Wêgrzynowicz M, Wang N, et al. GPR30 regulates glutamate transporter GLT-1 expression in rat primary astrocytes. J Biol Chem 2012; 287(32): 26817-28.
[http://dx.doi.org/10.1074/jbc.M112.341867] [PMID: 22645130]
[105]
Uddin MS, Rahman MM, Jakaria M, et al. Estrogen signaling in Alzheimer’s disease: Molecular insights and therapeutic targets for Alzheimer’s dementia. Mol Neurobiol 2020; 57(6): 2654-70.
[http://dx.doi.org/10.1007/s12035-020-01911-8] [PMID: 32297302]
[106]
Wang H, Si L, Li X, et al. Overexpression of estrogen receptor beta alleviates the toxic effects of beta-amyloid protein on PC12 cells via non-hormonal ligands. Neural Regen Res 2012; 7(14): 1095-100.
[http://dx.doi.org/10.3969/j.issn.1673-5374.2012.14.008] [PMID: 25722700]
[107]
Sarkar S, Jun S, Simpkins JW. Estrogen amelioration of Aβ-induced defects in mitochondria is mediated by mitochondrial signaling pathway involving ERβ AKAP and Drp1. Brain Res 2015; 1616: 101-11.
[http://dx.doi.org/10.1016/j.brainres.2015.04.059] [PMID: 25964165]
[108]
Rickle A, Bogdanovic N, Volkman I, Winblad B, Ravid R, Cowburn RF. Akt activity in Alzheimer’s disease and other neurodegenerative disorders. Neuroreport 2004; 15(6): 955-9.
[http://dx.doi.org/10.1097/00001756-200404290-00005] [PMID: 15076714]
[109]
Long J, He P, Shen Y, Li R. New evidence of mitochondria dysfunction in the female Alzheimer’s disease brain: Deficiency of estrogen receptor-β. J Alzheimers Dis 2012; 30(3): 545-58.
[http://dx.doi.org/10.3233/JAD-2012-120283] [PMID: 22451324]
[110]
Hojo Y, Murakami G, Mukai H, et al. Estrogen synthesis in the brain--role in synaptic plasticity and memory. Mol Cell Endocrinol 2008; 290(1-2): 31-43.
[http://dx.doi.org/10.1016/j.mce.2008.04.017] [PMID: 18541362]
[111]
Tang MX, Jacobs D, Stern Y, et al. Effect of oestrogen during menopause on risk and age at onset of Alzheimer’s disease. Lancet 1996; 348(9025): 429-32.
[http://dx.doi.org/10.1016/S0140-6736(96)03356-9] [PMID: 8709781]
[112]
Rosario ER, Chang L, Stanczyk FZ, Pike CJ. Age-related testosterone depletion and the development of Alzheimer disease. JAMA 2004; 292(12): 1431-2.
[http://dx.doi.org/10.1001/jama.292.12.1431-b] [PMID: 15383512]
[113]
Li Y, Li S, Xu S, et al. Association of androgens and gonadotropins with amnestic mild cognitive impairment and probable Alzheimer’s disease in chinese elderly men. J Alzheimers Dis 2020; 78(1): 277-90.
[http://dx.doi.org/10.3233/JAD-200233] [PMID: 32986665]
[114]
Ruitenberg A, Ott A, van Swieten JC, Hofman A, Breteler MM. Incidence of dementia: Does gender make a difference? Neurobiol Aging 2001; 22(4): 575-80.
[http://dx.doi.org/10.1016/S0197-4580(01)00231-7] [PMID: 11445258]
[115]
Wu TW, Wang JM, Chen S, Brinton RD. 17Beta-estradiol induced Ca2+ influx via L-type calcium channels activates the Src/ERK/cyclic-AMP response element binding protein signal pathway and BCL-2 expression in rat hippocampal neurons: A potential initiation mechanism for estrogen-induced neuroprotection. Neuroscience 2005; 135(1): 59-72.
[http://dx.doi.org/10.1016/j.neuroscience.2004.12.027] [PMID: 16084662]
[116]
Sever R, Glass CK. Signaling by nuclear receptors. Cold Spring Harb Perspect Biol 2013; 5(3): a016709.
[http://dx.doi.org/10.1101/cshperspect.a016709] [PMID: 23457262]
[117]
Baumbach JL, Zovkic IB. Hormone-epigenome interactions in behavioural regulation. Horm Behav 2020; 118: 104680.
[http://dx.doi.org/10.1016/j.yhbeh.2020.104680] [PMID: 31927018]
[118]
Zhang X, Ho SM. Epigenetics meets endocrinology. J Mol Endocrinol 2011; 46(1): R11-32.
[http://dx.doi.org/10.1677/JME-10-0053] [PMID: 21322125]
[119]
Bartlett AA, Lapp HE, Hunter RG. Epigenetic mechanisms of the glucocorticoid receptor. Trends Endocrinol Metab 2019; 30(11): 807-18.
[http://dx.doi.org/10.1016/j.tem.2019.07.003] [PMID: 31699238]
[120]
Stefanelli G, Azam AB, Walters BJ, et al. Learning and age-related changes in genome-wide H2A.Z binding in the mouse hippocampus. Cell Rep 2018; 22(5): 1124-31.
[http://dx.doi.org/10.1016/j.celrep.2018.01.020] [PMID: 29386101]
[121]
Ramzan F, Baumbach J, Monks AD, Zovkic IB. Histone H2A.Z is required for androgen receptor-mediated effects on fear memory. Neurobiol Learn Mem 2020; 175: 107311.
[http://dx.doi.org/10.1016/j.nlm.2020.107311] [PMID: 32916283]
[122]
Xu N, Chua AK, Jiang H, Liu NA, Goodarzi MO. Early embryonic androgen exposure induces transgenerational epigenetic and metabolic changes. Mol Endocrinol 2014; 28(8): 1329-36.
[http://dx.doi.org/10.1210/me.2014-1042] [PMID: 24992182]
[123]
Pérez SE, Chen EY, Mufson EJ. Distribution of estrogen receptor alpha and beta immunoreactive profiles in the postnatal rat brain. Brain Res Dev Brain Res 2003; 145(1): 117-39.
[http://dx.doi.org/10.1016/S0165-3806(03)00223-2] [PMID: 14519499]
[124]
Wilson ME, Rosewell KL, Kashon ML, Shughrue PJ, Merchenthaler I, Wise PM. Age differentially influences estrogen receptor-alpha (ERalpha) and estrogen receptor-beta (ERbeta) gene expression in specific regions of the rat brain. Mech Ageing Dev 2002; 123(6): 593-601.
[http://dx.doi.org/10.1016/S0047-6374(01)00406-7] [PMID: 11850023]
[125]
Kumar RC, Thakur MK. Androgen receptor mRNA is inversely regulated by testosterone and estradiol in adult mouse brain. Neurobiol Aging 2004; 25(7): 925-33.
[http://dx.doi.org/10.1016/j.neurobiolaging.2003.10.011] [PMID: 15212846]

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