Estrogen receptor β in Alzheimer’s disease: From mechanisms to therapeutics

Adams, 2002, Estrogen and aging affect the subcellular distribution of estrogen receptor-alpha in the hippocampus of female rats, J. Neurosci., 22, 3608, 10.1523/JNEUROSCI.22-09-03608.2002 Aguirre, 2010, Progesterone inhibits estrogen-mediated neuroprotection against excitotoxicity by down-regulating estrogen receptor-beta, J. Neurochem., 115, 1277, 10.1111/j.1471-4159.2010.07038.x Aguirre, 2009, Progesterone reverses 17beta-estradiol-mediated neuroprotection and BDNF induction in cultured hippocampal slices, Eur. J. Neurosci., 29, 447, 10.1111/j.1460-9568.2008.06591.x Altmann, 2014, Sex modifies the APOE-related risk of developing Alzheimer disease, Ann. Neurol., 75, 563, 10.1002/ana.24135 Artero, 2008, Risk profiles for mild cognitive impairment and progression to dementia are gender specific, J. Neurol. Neurosurg. Psychiatry, 79, 979, 10.1136/jnnp.2007.136903 Bardin, 2004, Loss of ERbeta expression as a common step in estrogen-dependent tumor progression, Endocr. Relat. Cancer, 11, 537, 10.1677/erc.1.00800 Barnes, 2005, Sex differences in the clinical manifestations of Alzheimer disease pathology, Arch. Gen. Psychiatry, 62, 685, 10.1001/archpsyc.62.6.685 Berti, 2011, Structural brain changes in normal individuals with a maternal history of Alzheimer’s, Neurobiol. Aging, 32, 2325, 10.1016/j.neurobiolaging.2011.01.001 Binder, 2004, Brain-derived neurotrophic factor, Growth Factors, 22, 123, 10.1080/08977190410001723308 Bretsky, 1999, Evidence for an interaction between apolipoprotein E genotype, gender, and Alzheimer disease, Alzheimer Dis. Assoc. Disord., 13, 216, 10.1097/00002093-199910000-00007 Brinton, 2005, Investigative models for determining hormone therapy-induced outcomes in brain: evidence in support of a healthy cell bias of estrogen action, Ann. N. Y. Acad. Sci., 1052, 57, 10.1196/annals.1347.005 Brinton, 2008, The healthy cell bias of estrogen action: mitochondrial bioenergetics and neurological implications, Trends Neurosci., 31, 529, 10.1016/j.tins.2008.07.003 Brinton, 2009, Estrogen-induced plasticity from cells to circuits: predictions for cognitive function, Trends Pharmacol. Sci., 30, 212, 10.1016/j.tips.2008.12.006 Brookmeyer, 2011, National estimates of the prevalence of Alzheimer’s disease in the United States, Alzheimers Dement., 7, 61, 10.1016/j.jalz.2010.11.007 Burkhardt, 2004, Oestrogen replacement therapy may improve memory functioning in the absence of APOE epsilon4, J. Alzheimer’s Dis., 6, 221, 10.3233/JAD-2004-6302 Carter, 2012, Sex and gender differences in Alzheimer’s disease: recommendations for future research, J. Womens Health (Larchmt.), 21, 1018, 10.1089/jwh.2012.3789 Chang, 2014, APOE interacts with age to modify rate of decline in cognitive and brain changes in Alzheimer’s disease, Alzheimers Dement., 10, 336, 10.1016/j.jalz.2013.05.1763 Chapman, 2011, Women have farther to fall: gender differences between normal elderly and Alzheimer’s disease in verbal memory engender better detection of Alzheimer’s disease in women, J. Int. Neuropsychol. Soc., 1 Choi, 2014, A three-dimensional human neural cell culture model of Alzheimer’s disease, Nature, 515, 274, 10.1038/nature13800 Claxton, 2013, Sex and ApoE genotype differences in treatment response to two doses of intranasal insulin in adults with mild cognitive impairment or Alzheimer’s disease, J. Alzheimers Dis., 35, 789, 10.3233/JAD-122308 Corder, 1993, Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families, Science, 261, 921, 10.1126/science.8346443 Day, 2005, Beta estrogen receptor knockout (BERKO) mice present attenuated hippocampal CA1 long-term potentiation and related memory deficits in contextual fear conditioning, Behav. Brain Res., 164, 128, 10.1016/j.bbr.2005.05.011 Dresner-Pollak, 2009, Estrogen receptor beta gene variant is associated with vascular dementia in elderly women, Genet. Test Mol. Biomark., 13, 339, 10.1089/gtmb.2008.0129 Elcoroaristizabal Martin, 2011, Progression from amnesic mild cognitive impairment to Alzheimer’s disease: ESR1 and ESR2 polymorphisms and APOE gene, Dement. Geriatr. Cogn. Disord., 32, 332, 10.1159/000335541 Espeland, 2004, Conjugated equine estrogens and global cognitive function in postmenopausal women: Women’s Health Initiative Memory Study, J. Am. Med. Assoc., 291, 2959, 10.1001/jama.291.24.2959 Farrer, 1997, Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium, J. Am. Med. Assoc., 278, 1349, 10.1001/jama.1997.03550160069041 Fernandez-Martinez, 2013, Oestrogen receptor polymorphisms are an associated risk factor for mild cognitive impairment and Alzheimer disease in women APOE {varepsilon}4 carriers: a case-control study, BMJ Open, 3, e003200, 10.1136/bmjopen-2013-003200 Forsell, 2001, Investigations of a CA repeat in the oestrogen receptor beta gene in patients with Alzheimer’s disease, Eur. J. Hum. Genet., 9, 802, 10.1038/sj.ejhg.5200714 Fox, 2008, ERbeta in breast cancer-onlooker, passive player, or active protector?, Steroids, 73, 1039, 10.1016/j.steroids.2008.04.006 Franco, 2014, Successful therapies for Alzheimer’s disease: why so many in animal models and none in humans?, Front. Pharmacol., 5, 146, 10.3389/fphar.2014.00146 Gallo, 2012, Estrogen receptor Beta in cancer: an attractive target for therapy, Curr. Pharm. Des., 18, 2734, 10.2174/138161212800626139 Games, 1995, Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein, Nature, 373, 523, 10.1038/373523a0 Gao, 1998, The relationship between age, sex, and the incidence of dementia and Alzheimer disease: a meta-analysis, Arch. Gen. Psychiatry, 55, 809, 10.1001/archpsyc.55.9.809 George, 2013, Nonsteroidal selective androgen receptor modulators and selective estrogen receptor beta agonists moderate cognitive deficits and amyloid-beta levels in a mouse model of Alzheimer’s disease, ACS Chem. Neurosc., 4, 1537, 10.1021/cn400133s Goumidi, 2011, Study of estrogen receptor-alpha and receptor-beta gene polymorphisms on Alzheimer’s disease, J. Alzheimers Dis., 26, 431, 10.3233/JAD-2011-110362 Grady, 2009, MF101, a selective estrogen receptor beta modulator for the treatment of menopausal hot flushes: a phase II clinical trial, Menopause, 16, 458, 10.1097/gme.0b013e31818e64dd Green, 1986, Human oestrogen receptor cDNA: sequence, expression and homology to v-erb-A, Nature, 320, 134, 10.1038/320134a0 Gustafsson, 2003, What pharmacologists can learn from recent advances in estrogen signaling, Trends Pharmacol. Sci., 24, 479, 10.1016/S0165-6147(03)00229-3 Hall, 2012, Bonston naming test: gender differences in older adults with and without Alzheimer’s dementia, Psychology, 3, 485, 10.4236/psych.2012.36068 Hartman, 2009, Estrogen receptor beta in breast cancer-diagnostic and therapeutic implications, Steroids, 74, 635, 10.1016/j.steroids.2009.02.005 Hartman, 2012, Current concepts and significance of estrogen receptor beta in prostate cancer, Steroids, 77, 1262, 10.1016/j.steroids.2012.07.002 Hestiantoro, 2004, Changes in estrogen receptor-alpha and -beta in the infundibular nucleus of the human hypothalamus are related to the occurrence of Alzheimer’s disease neuropathology, J. Clin. Endocrinol. Metab., 89, 1912, 10.1210/jc.2003-030862 Honea, 2011, Progressive regional atrophy in normal adults with a maternal history of Alzheimer disease, Neurology, 76, 822, 10.1212/WNL.0b013e31820e7b74 Hsia, 1999, Plaque-independent disruption of neural circuits in Alzheimer’s disease mouse models, Proc. Natl. Acad. Sci. U. S. A., 96, 3228, 10.1073/pnas.96.6.3228 Hsiao, 1996, Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice, Science, 274, 99, 10.1126/science.274.5284.99 Irvine, 2012, Greater cognitive deterioration in women than men with Alzheimer’s disease: a meta analysis, J. Clin. Exp. Neuropsychol., 34, 989, 10.1080/13803395.2012.712676 Irvine, 2012, Greater cognitive deterioration in women than men with Alzheimer’s disease: a meta analysis, J. Clin. Exp. Neuropsychol., 10.1080/13803395.2012.712676 Jacobs, 2013, Accelerated cell aging in female APOE-epsilon4 carriers: implications for hormone therapy use, PLoS One, 8, e54713, 10.1371/journal.pone.0054713 Jacome, 2010, Estradiol and ERbeta agonists enhance recognition memory, and DPN, an ERbeta agonist, alters brain monoamines, Neurobiol. Learn. Mem., 94, 488, 10.1016/j.nlm.2010.08.016 Janicki, 2014, Estrogen receptor beta variants modify risk for Alzheimer’s disease in a multiethnic female cohort, J. Alzheimers Dis., 40, 83, 10.3233/JAD-130551 Johnson, 1998, Initiation and propagation stages of beta-amyloid are associated with distinctive apolipoprotein E, age, and gender profiles, Brain Res., 798, 18, 10.1016/S0006-8993(98)00363-1 Kalesnykas, 2005, The effect of aging on the subcellular distribution of estrogen receptor-alpha in the cholinergic neurons of transgenic and wild-type mice, Eur. J. Neurosci., 21, 1437, 10.1111/j.1460-9568.2005.03953.x Kang, 2012, Postmenopausal hormone therapy, timing of initiation, APOE and cognitive decline, Neurobiol. Aging, 33, 1129, 10.1016/j.neurobiolaging.2010.10.007 Kennedy, 2014, Effect of APOE genotype status on targeted clinical trials outcomes and efficiency in dementia and mild cognitive impairment resulting from Alzheimer’s disease, Alzheimers Dement., 10, 349, 10.1016/j.jalz.2013.03.003 Kim, 2009, The role of apolipoprotein E in Alzheimer’s disease, Neuron, 63, 287, 10.1016/j.neuron.2009.06.026 Kuiper, 1996, Cloning of a novel receptor expressed in rat prostate and ovary, Proc. Natl. Acad. Sci. U. S. A., 93, 5925, 10.1073/pnas.93.12.5925 Kunzler, 2014, APOE modulates the effect of estrogen therapy on Abeta accumulation EFAD-Tg mice, Neurosci. Lett., 560, 131, 10.1016/j.neulet.2013.12.032 Lambert, 2004, The allelic modulation of apolipoprotein E expression by oestrogen: potential relevance for Alzheimer’s disease, J. Med. Genet., 41, 104, 10.1136/jmg.2003.005033 Lambert, 2001, Are the estrogen receptors involved in Alzheimer’s disease?, Neurosci. Lett., 306, 193, 10.1016/S0304-3940(01)01806-7 Laurijssens, 2013, Animal models of Alzheimer’s disease and drug development, Drug Discov. Today Technol., 10, e319, 10.1016/j.ddtec.2012.04.001 Lee, 2013, An update of animal models of Alzheimer disease with a reevaluation of plaque depositions, Exp. Neurobiol., 22, 84, 10.5607/en.2013.22.2.84 Leitman, 2012, MF 101: a multi-component botanical selective estrogen receptor beta modulator for the treatment of menopausal vasomotor symptoms, Expert Opin. Investig. Drugs, 10.1517/13543784.2012.685652 Levin-Allerhand, 2001, Brain region-specific up-regulation of mouse apolipoprotein E by pharmacological estrogen treatments, J. Neurochem., 79, 796, 10.1046/j.1471-4159.2001.00627.x Liu, 2013, Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy, Nat. Rev. Neurol., 9, 106, 10.1038/nrneurol.2012.263 Liu, 2008, Activation of estrogen receptor-beta regulates hippocampal synaptic plasticity and improves memory, Nat. Neurosci., 11, 334, 10.1038/nn2057 Long, 2012, New evidence of mitochondria dysfunction in the female Alzheimer’s disease brain: deficiency of estrogen receptor-beta, J. Alzheimers Dis., 30, 545, 10.3233/JAD-2012-120283 Lu, 2003, BDNF and activity-dependent synaptic modulation, Learn. Mem., 10, 86, 10.1101/lm.54603 Luckhaus, 2006, Estrogen receptor beta gene (ESRbeta) 3′-UTR variants in Alzheimer disease, Alzheimer Dis. Assoc. Disord., 20, 322, 10.1097/01.wad.0000213861.12484.33 MacLennan, 2006, Hormone therapy, timing of initiation, and cognition in women aged older than 60 years: the REMEMBER pilot study, Menopause, 13, 28, 10.1097/01.gme.0000191204.38664.61 Manson, 2007, Estrogen therapy and coronary-artery calcification, N. Engl. J. Med., 356, 2591, 10.1056/NEJMoa071513 McBride, R., September 14, 2012. Pharma counts just 3 Alzheimer’s drug wins in 13 yeasr (101 losses). http://www.fiercebiotech.com/story/pharma-counts-just-3-alzheimers-drug-wins-13-years-101-losses/2012-09-14. McEwen, 2002, Estrogen actions throughout the brain, Recent Prog. Horm. Res., 57, 357, 10.1210/rp.57.1.357 McPherson, 2010, Estrogen receptor-beta activated apoptosis in benign hyperplasia and cancer of the prostate is androgen independent and TNFalpha mediated, Proc. Natl. Acad. Sci. U. S. A., 107, 3123, 10.1073/pnas.0905524107 Mielke, 2012, Effects of food and drug administration-approved medications for Alzheimer’s disease on clinical progression, Alzheimers Dement., 8, 180, 10.1016/j.jalz.2011.02.011 Milner, 2001, Ultrastructural evidence that hippocampal alpha estrogen receptors are located at extranuclear sites, J. Comp. Neurol., 429, 355, 10.1002/1096-9861(20010115)429:3<355::AID-CNE1>3.0.CO;2-# Mortensen, 2001, A gender difference in the association between APOE genotype and age-related cognitive decline, Neurology, 57, 89, 10.1212/WNL.57.1.89 Mosconi, 2010, Maternal transmission of Alzheimer’s disease: prodromal metabolic phenotype and the search for genes, Hum. Genom., 4, 170, 10.1186/1479-7364-4-3-170 Mosconi, 2006, Hypometabolism exceeds atrophy in presymptomatic early-onset familial Alzheimer’s disease, J. Nucl. Med., 47, 1778 Mullard, 2012, Sting of Alzheimer’s failures offset by upcoming prevention trials, Nat. Rev. Drug Discov., 11, 657, 10.1038/nrd3842 Murer, 2001, Brain-derived neurotrophic factor in the control human brain, and in Alzheimer’s disease and Parkinson’s disease, Prog. Neurobiol., 63, 71, 10.1016/S0301-0082(00)00014-9 Nathan, 2004, Estrogen facilitates neurite extension via apolipoprotein E in cultured adult mouse cortical neurons, Endocrinology, 145, 3065, 10.1210/en.2003-1707 Neurology, A.A.O., 2007. Estrogen Use Before 65 Linked to Reduced Risk of Alzheimer’s Disease. https://www.aan.com/PressRoom/Home/PressRelease/471. Nilsen, 2004, Mitochondria as therapeutic targets of estrogen action in the central nervous system, Curr. Drug Targets CNS Neurol. Disord., 3, 297, 10.2174/1568007043337193 Nilsen, 2005, Impact of clinically relevant progestins on the neural effects of estradiol and the signaling pathways involved, Drug News Perspect., 18, 545, 10.1358/dnp.2005.18.9.948450 Nilsson, 2011, Development of subtype-selective oestrogen receptor-based therapeutics, Nat. Rev. Drug Discov., 10, 778, 10.1038/nrd3551 Nishio, 2004, Subcellular localization of estrogen receptor beta in mouse hippocampus, Neurosci. Lett., 355, 109, 10.1016/j.neulet.2003.10.064 Oakley, 2006, Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation, J. Neurosci., 26, 10129, 10.1523/JNEUROSCI.1202-06.2006 Oddo, 2003, Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction, Neuron, 39, 409, 10.1016/S0896-6273(03)00434-3 Osterlund, 2000, The human brain has distinct regional expression patterns of estrogen receptor alpha mRNA isoforms derived from alternative promoters, J. Neurochem., 75, 1390, 10.1046/j.1471-4159.2000.0751390.x Osterlund, 2000, Estrogen receptor beta (ERbeta) messenger ribonucleic acid (mRNA) expression within the human forebrain: distinct distribution pattern to ERalpha mRNA, J. Clin. Endocrinol. Metab., 85, 3840 Payami, 1996, Gender difference in apolipoprotein E-associated risk for familial Alzheimer disease: a possible clue to the higher incidence of Alzheimer disease in women, Am. J. Hum. Genet., 58, 803 Pinton, 2009, Estrogen receptor-beta affects the prognosis of human malignant mesothelioma, Cancer Res., 69, 4598, 10.1158/0008-5472.CAN-08-4523 Pinton, 2010, Estrogen receptor beta exerts tumor repressive functions in human malignant pleural mesothelioma via EGFR inactivation and affects response to gefitinib, PLoS One, 5, e14110, 10.1371/journal.pone.0014110 Pirskanen, 2005, Estrogen receptor beta gene variants are associated with increased risk of Alzheimer’s disease in women, Eur. J. Hum. Genet., 13, 1000, 10.1038/sj.ejhg.5201447 Poirier, 1993, Apolipoprotein E polymorphism and Alzheimer’s disease, Lancet, 342, 697, 10.1016/0140-6736(93)91705-Q Prins, 2008, The role of estrogens and estrogen receptors in normal prostate growth and disease, Steroids, 73, 233, 10.1016/j.steroids.2007.10.013 Rapp, 2003, Effect of estrogen plus progestin on global cognitive function in postmenopausal women: the Women’s Health Initiative Memory Study: a randomized controlled trial, J. Am. Med. Assoc., 289, 2663, 10.1001/jama.289.20.2663 Regitz-Zagrosek, 2012, Sex and gender differences in clinical medicine, Handb. Exp. Pharmacol., 3 Rhodes, 2006, ERbeta-selective SERMs produce mnemonic-enhancing effects in the inhibitory avoidance and water maze tasks, Neurobiol. Learn. Mem., 85, 183, 10.1016/j.nlm.2005.10.003 Rice, S., January 25, 2014. As drug trials fail, Alzheimer’s researchers look toward prevention. http://www.modernhealthcare.com/article/20140125/MAGAZINE/301259969#. Rissman, 2002, Disruption of estrogen receptor beta gene impairs spatial learning in female mice, Proc. Natl. Acad. Sci. U. S. A., 99, 3996, 10.1073/pnas.012032699 Rossouw, 2007, Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause, J. Am. Med. Assoc., 297, 1465, 10.1001/jama.297.13.1465 Ryan, 2013, Prospective analysis of the association between estrogen receptor gene variants and the risk of cognitive decline in elderly women, Eur. Neuropsychopharmacol., 23, 1763, 10.1016/j.euroneuro.2013.06.003 Ryan, 2014, Estrogen receptor polymorphisms and incident dementia: the prospective 3C study, Alzheimers Dement., 10, 27, 10.1016/j.jalz.2012.12.008 Ryan, 2009, Characteristics of hormone therapy, cognitive function, and dementia: the prospective 3C Study, Neurology, 73, 1729, 10.1212/WNL.0b013e3181c34b0c Savaskan, 2001, Hippocampal estrogen beta-receptor immunoreactivity is increased in Alzheimer’s disease, Brain Res., 908, 113, 10.1016/S0006-8993(01)02610-5 Schmidt, 2008, Sex differences in Alzheimer’s disease, Neuropsychiatric, 22, 1 Schnabel, J., July 8, 2013. Why do all the large Alzheimer’s drug trials fail? http://www.dana.org/News/Why_Do_All_the_Large_Alzheimer_s_Drug_Trials_Fail_/. Selfridge, 2013, Role of mitochondrial homeostasis and dynamics in Alzheimer’s disease, Neurobiol. Dis., 51, 3, 10.1016/j.nbd.2011.12.057 Selman, 2009, Ribosomal protein S6 kinase 1 signaling regulates mammalian life span, Science, 326, 140, 10.1126/science.1177221 Shumaker, 2004, Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women’s Health Initiative Memory Study, J. Am. Med. Assoc., 291, 2947, 10.1001/jama.291.24.2947 Shumaker, 2003, Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women’s Health Initiative Memory Study: a randomized controlled trial, J. Am. Med. Assoc., 289, 2651, 10.1001/jama.289.20.2651 Simpkins, 2008, Mitochondrial mechanisms of estrogen neuroprotection, Brain Res. Rev., 57, 421, 10.1016/j.brainresrev.2007.04.007 Simpkins, 2005, Estrogens progestins, menopause and neurodegeneration: basic and clinical studies, Cell. Mol. Life Sci., 62, 271, 10.1007/s00018-004-4382-2 Sohrabji, 1995, Identification of a putative estrogen response element in the gene encoding brain-derived neurotrophic factor, Proc. Natl. Acad. Sci. U.S.A., 92, 11110, 10.1073/pnas.92.24.11110 Struble, 2008, Apolipoprotein E may be a critical factor in hormone therapy neuroprotection, Front. Biosci., 13, 5387, 10.2741/3088 Struble, 2003, Regionally specific modulation of brain apolipoprotein E in the mouse during the estrous cycle and by exogenous 17beta estradiol, Exp. Neurol., 183, 638, 10.1016/S0014-4886(03)00215-2 Swerdlow, 2013, The Alzheimer’s disease mitochondrial cascade hypothesis:progress and perspectives, Biochim. Biophys. Acta Tapia-Arancibia, 2008, New insights into brain BDNF function in normal aging and Alzheimer disease, Brain Res. Rev., 59, 201, 10.1016/j.brainresrev.2008.07.007 Taylor, 2000, Immunolocalisation of oestrogen receptor beta in human tissues, J. Mol. Endocrinol., 24, 145, 10.1677/jme.0.0240145 Thies, 2013, Alzheimer’s disease facts and figures, Alzheimers Dement., 9, 208 Tian, 2013, Estrogen receptor beta treats Alzheimer’s disease, Neural Regen. Res., 8, 420 Toran-Allerand, 1992, Estrogen receptors colocalize with low-affinity nerve growth factor receptors in cholinergic neurons of the basal forebrain, Proc. Natl. Acad. Sci. U. S. A., 89, 4668, 10.1073/pnas.89.10.4668 Ungar, 2014, Apolipoprotein E, gender, and Alzheimer’s disease: an overlooked, but potent and promising interaction, Brain Imaging Behav., 8, 262, 10.1007/s11682-013-9272-x Valen-Sendstad, 2010, Effects of hormone therapy on depressive symptoms and cognitive functions in women with Alzheimer disease: a 12 month randomized, double-blind, placebo-controlled study of low-dose estradiol and norethisterone, Am. J. Geriatr. Psychiatry, 18, 11, 10.1097/JGP.0b013e3181beaaf4 Walf, 2007, Administration of estrogen receptor beta-specific selective estrogen receptor modulators to the hippocampus decrease anxiety and depressive behavior of ovariectomized rats, Pharmacol. Biochem. Behav., 86, 407, 10.1016/j.pbb.2006.07.003 Walf, 2008, Estradiol or diarylpropionitrile decrease anxiety-like behavior of wildtype, but not estrogen receptor beta knockout, mice, Behav. Neurosci., 122, 974, 10.1037/a0012749 Wang, 2006, Activation of estrogen receptor alpha increases and estrogen receptor beta decreases apolipoprotein E expression in hippocampus in vitro and in vivo, Proc. Natl. Acad. Sci. U. S. A., 103, 16983, 10.1073/pnas.0608128103 Wang, 2001, Morphological abnormalities in the brains of estrogen receptor beta knockout mice, Proc. Natl. Acad. Sci. U. S. A., 98, 2792, 10.1073/pnas.041617498 Wang, 2003, Estrogen receptor (ER) beta knockout mice reveal a role for ERbeta in migration of cortical neurons in the developing brain, Proc. Natl. Acad. Sci. U. S. A., 100, 703, 10.1073/pnas.242735799 Ward, 2012, Prevalence of apolipoprotein E4 genotype and homozygotes (APOE e4/4) among patients diagnosed with Alzheimer’s disease: a systematic review and meta-analysis, Neuroepidemiology, 38, 1, 10.1159/000334607 Waters, 2011, Estrogen and aging affect the synaptic distribution of estrogen receptor beta-immunoreactivity in the CA1 region of female rat hippocampus, Brain Res., 1379, 86, 10.1016/j.brainres.2010.09.069 Weihua, 2003, Update on estrogen signaling, FEBS Lett., 546, 17, 10.1016/S0014-5793(03)00436-8 Wilson, 2002, Age differentially influences estrogen receptor-alpha (ERalpha) and estrogen receptor-beta (ERbeta) gene expression in specific regions of the rat brain, Mech. Ageing Dev., 123, 593, 10.1016/S0047-6374(01)00406-7 Yaffe, 1997, Apolipoprotein E phenotype and cognitive decline in a prospective study of elderly community women, Arch. Neurol., 54, 1110, 10.1001/archneur.1997.00550210044011 Yaffe, 2000, Estrogen use, APOE, and cognitive decline: evidence of gene-environment interaction, Neurology, 54, 1949, 10.1212/WNL.54.10.1949 Yaffe, 2009, Estrogen receptor genotype and risk of cognitive impairment in elders: findings from the Health ABC Study, Neurobiol. Aging., 30, 607, 10.1016/j.neurobiolaging.2007.08.003 Yamaguchi, 2012, Changes in oestrogen receptor-beta mRNA expression in male rat brain with age, J. Neuroendocrinol., 24, 310, 10.1111/j.1365-2826.2011.02231.x Yang, 2004, Mitochondrial localization of estrogen receptor beta, Proc. Natl. Acad. Sci. U. S. A., 101, 4130, 10.1073/pnas.0306948101 Yao, 2009, Mitochondrial bioenergetic deficit precedes Alzheimer’s pathology in female mouse model of Alzheimer’s disease, Proc. Natl. Acad. Sci. U. S. A., 106, 14670, 10.1073/pnas.0903563106 Yoshii, 2010, Postsynaptic BDNF-TrkB signaling in synapse maturation, plasticity, and disease, Dev. Neurobiol., 70, 304 Younes, 2011, Estrogen receptor beta, Arch. Pathol. Lab. Med., 135, 63, 10.5858/2010-0448-RAR.1 Yue, 2007, Effects of long-term, low-dose sex hormone replacement therapy on hippocampus and cognition of postmenopausal women of different apoE genotypes, Acta Pharmacol. Sin., 28, 1129, 10.1111/j.1745-7254.2007.00618.x Zandi, 2002, Reduced incidence of AD with NSAID but not H2 receptor antagonists: the Cache County Study, Neurology, 59, 880, 10.1212/WNL.59.6.880 Zandi, 2002, Hormone replacement therapy and incidence of Alzheimer disease in older women: the Cache County Study, J. Am. Med. Assoc., 288, 2123, 10.1001/jama.288.17.2123 Zhao, 2005, Structure-based virtual screening for plant-based ERbeta-selective ligands as potential preventative therapy against age-related neurodegenerative diseases, J. Med. Chem., 48, 3463, 10.1021/jm0490538 Zhao, 2006, Estrogen receptor beta as a therapeutic target for promotion of neurogenesis and prevention of neurodegeneration, Drug Dev. Res., 66, 103, 10.1002/ddr.20049 Zhao, 2006, Select estrogens within the complex formulation of conjugated equine estrogens (Premarin) are protective against neurodegenerative insults: implications for a composition of estrogen therapy to promote neuronal function and prevent Alzheimer’s disease, BMC Neurosci., 7, 24, 10.1186/1471-2202-7-24 Zhao, 2007, Estrogen receptor alpha and beta differentially regulate intracellular Ca(2+) dynamics leading to ERK phosphorylation and estrogen neuroprotection in hippocampal neurons, Brain Res., 1172, 48, 10.1016/j.brainres.2007.06.092 Zhao, 2007, WHI and WHIMS follow-up and human studies of soy isoflavones on cognition, Expert Rev. Neurother., 7, 1549, 10.1586/14737175.7.11.1549 Zhao, 2009, In search of estrogen alternatives for the brain, 93 Zhao, 2007, Design, synthesis, and estrogenic activity of a novel estrogen receptor modulator-a hybrid structure of 17beta-estradiol and vitamin E in hippocampal neurons, J. Med. Chem., 50, 4471, 10.1021/jm070546x Zhao, 2009, A select combination of clinically relevant phytoestrogens enhances estrogen receptor beta-binding selectivity and neuroprotective activities in vitro and in vivo, Endocrinology, 150, 770, 10.1210/en.2008-0715 Zhao, 2013, Early intervention with an estrogen receptor beta-selective phytoestrogenic formulation prolongs survival, improves spatial recognition memory, and slows progression of amyloid pathology in a female mouse model of Alzheimer’s disease, J. Alzheimers Dis., 37, 403, 10.3233/JAD-122341 Zhao, 2011, Estrogen receptor beta-selective phytoestrogenic formulation prevents physical and neurological changes in a preclinical model of human menopause, Menopause, 18, 1131, 10.1097/gme.0b013e3182175b66 Zhao, 2012, Continuous versus cyclic progesterone exposure differentially regulates hippocampal gene expression and functional profiles, PLoS One, 7, e31267, 10.1371/journal.pone.0031267 Zhao, 2005, Selective estrogen receptor modulators (SERMs) for the brain: current status and remaining challenges for developing NeuroSERMs, Brain Res. Brain Res. Rev., 49, 472, 10.1016/j.brainresrev.2005.01.009 Zhao, 2006, Estrogenic agonist activity of ICI 182,780 (Faslodex) in hippocampal neurons: implications for basic science understanding of estrogen signaling and development of estrogen modulators with a dual therapeutic profile, J. Pharmacol. Exp. Ther., 319, 1124, 10.1124/jpet.106.109504 Zhao, 2004, Estrogen receptor subtypes alpha and beta contribute to neuroprotection and increased Bcl-2 expression in primary hippocampal neurons, Brain Res., 1010, 22, 10.1016/j.brainres.2004.02.066 Zhao, 2011, 17beta-Estradiol regulates insulin-degrading enzyme expression via an ERbeta/PI3-K pathway in hippocampus: relevance to Alzheimer’s prevention, Neurobiol. Aging, 32, 1949, 10.1016/j.neurobiolaging.2009.12.010 Zhao, 2011, Estrogen receptor-Beta variants are associated with increased risk of Alzheimer’s disease in women with down syndrome, Dement. Geriatr. Cogn. Disord., 32, 241, 10.1159/000334522