Abstract
Alzheimer’s disease (AD) is described as cognitive and memory impairments with a sex-related epidemiological profile, affecting two times more women than men. There is emerging evidence that alternations in the hippocampal neurogenesis occur at the early stage of AD. Therapies that may effectively slow, stop, or regenerate the dying neurons in AD are being extensively investigated in the last few decades, but none has yet been found to be effective. The regulation of endogenous neurogenesis is one of the main therapeutic targets for AD. Mounting evidence indicates that the neurosteroid estradiol (17β-estradiol) plays a supporting role in neurogenesis, neuronal activity, and synaptic plasticity of AD. This effect may provide preventive and/or therapeutic approaches for AD. In this article, we discuss the molecular mechanism of potential estradiol modulatory action on endogenous neurogenesis, synaptic plasticity, and cognitive function in AD.
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Aenlle KK, Kumar A, Cui L, Jackson TC, Foster TC (2007) Estrogen effects on cognition and hippocampal transcription in middle-aged mice. Neurobiol Aging 30(6):932–945. https://doi.org/10.1016/j.neurobiolaging.2007.09.004
Almey A, Milner TA, Brake WG (2015) Estrogen receptors in the central nervous system and their implication for dopamine-dependent cognition in females. Horm Behav 74:125–138. https://doi.org/10.1016/j.yhbeh.2015.06.010
Altman J (1969) Autoradiographic and histological studies of postnatal neurogenesis. IV. Cell proliferation and migration in the anterior forebrain, with special reference to persisting neurogenesis in the olfactory bulb. J Comp Neurol 137(4):433–457. https://doi.org/10.1002/cne.901370404
Altman J, Das GD (1965) Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol 124(3):319–335
Amakiri N, Kubosumi A, Tran J, Reddy PH (2019) Amyloid beta and microRNAs in Alzheimer’s disease. Front Neurosci 13:430. https://doi.org/10.3389/fnins.2019.00430
Anastasio TJ (2013) Exploring the contribution of estrogen to amyloid-Beta regulation: a novel multifactorial computational modeling approach. Front Pharmacol 4:16. https://doi.org/10.3389/fphar.2013.00016
Andrews-Zwilling Y, Bien-Ly N, Xu Q, Li G, Bernardo A, Yoon SY, Zwilling D, Yan TX, Chen L, Huang Y (2010) Apolipoprotein E4 causes age- and Tau-dependent impairment of GABAergic interneurons, leading to learning and memory deficits in mice. J Neurosci 30:13707–13717. https://doi.org/10.1523/JNEUROSCI.4040-10.2010
Azcoitia I, Yague J, Garcia-Segura LM (2011) Estradiol synthesis within the human brain. Neuroscience 191:139–147. https://doi.org/10.1016/j.neuroscience.2011.02.012
Banasr M, Hery M, Brezun JM, Daszuta A (2001) Serotonin mediates oestrogen stimulation of cell proliferation in the adult dentate gyrus. Eur J Neurosci 14:1417–1424. https://doi.org/10.1046/j.0953-816x.2001.01763.x
Barnea A, Roberts J (2001) Induction of functional and morphological expression of neuropeptide Y (NPY) in cortical cultures by brain-derived neurotrophic factor (BDNF): evidence for a requirement for extracellular-regulated kinase (ERK)-dependent and ERK-independent mechanisms. Brain Res 919:57–69. https://doi.org/10.1016/S0006-8993(01)02999-7
Barron AM, Pike CJ (2012) Sex hormones, aging, and Alzheimer’s disease. Front Biosci 4:976–997
Behl C, Skutella T, Frank LH, Post A, Widmann M, Newton CJ, Holsboer F (1997) Neuroprotection against oxidative stress by estrogens: structure-activity relationship. Mol Pharmacol 51:535–541. https://doi.org/10.1124/mol.51.4.535
Bhattacherjee A, Liao Z, Smith PG (2014) Trophic factor and hormonal regulation of neurite outgrowth in sensory neuron-like 50B11 cells. Neurosci Lett 558:120–125. https://doi.org/10.1016/j.neulet.2013.11.018
Bi R, Broutman G, Foy MR, Thompson RF, Baudry M (2000) The tyrosine kinase and mitogen-activated protein kinase pathways mediate multiple effects of estrogen in hippocampus. Proc Natl Acad Sci USA 97:3602–3607. https://doi.org/10.1073/pnas.060034497
Bi R, Foy MR, Vouimba RM, Thompson RF, Baudry M (2001) Cyclic changes in estradiol regulate synaptic plasticity through the MAP kinase pathway. Proc Natl Acad Sci USA 98(23):13391–13395. https://doi.org/10.1073/pnas.241507698
Bi R, Foy MR, Thompson RF, Baudry M (2003) Effects of estrogen, age, and calpain on MAP kinase and NMDA receptors in female rat brain. Neurobiol Aging 24(7):977–983. https://doi.org/10.1016/S0197-4580(03)00012-5
Blaustein JD (1992) Cytoplasmic estrogen receptors in rat brain: immunocytochemical evidence using three antibodies with distinct epitopes. Endocrinology 131:1336–1342. https://doi.org/10.1210/endo.131.3.1380440
Bless EP, Yang J, Acharya KD, Nettles SA, Vassoler FM, Byrnes EM, Tetel MJ (2016) Adult neurogenesis in the female mouse hypothalamus: estradiol and high-fat diet alter the generation of newborn neurons expressing estrogen receptor alpha. eNeuro. https://doi.org/10.1523/ENEURO.0027-16.2016
Blurton-Jones M, Kuan P, Tuszynski M (2004) Anatomical evidence for transsynaptic influences of estrogen on brain-derived neurotrophic factor expression. J Comp Neurol 468:347–360. https://doi.org/10.1002/cne.10989
Boldrini M, Fulmore CA, Tartt AN, Simeon LR, Pavlova I, Poposka V, Rosoklija GB, Stankov A, Arango V, Dwork AJ, Hen R, Mann JJ (2018) Human hippocampal neurogenesis persists throughout aging. Cell Stem Cell 22(4):589–599. https://doi.org/10.1016/j.stem.2018.03.015
Brinton RD, Chen S, Montoya M, Hsieh D, Minaya J (2000) The estrogen replacement therapy of the Women’s Health Initiative promotes the cellular mechanisms of memory and neuronal survival in neurons vulnerable to Alzheimer’s disease. Maturitas 34:S35–S52. https://doi.org/10.1016/S0378-5122(00)00107-9
Brinton RD, Thompson RF, Foy MR, Baudry M, Wang J, Finch CE, Morgan TE, Pike CJ, Mack WJ, Stanczyk FZ, Nilsen J (2008) Progesterone receptors: form and function in brain. Front Neuroendocrinol 29(2):313–339. https://doi.org/10.1016/j.yfrne.2008.02.001
Briz V, Baudry M (2014) Estrogen regulates protein synthesis and actin polymerization in hippocampal neurons through different molecular mechanisms. Front Endocrinol 5:22. https://doi.org/10.3389/fendo.2014.00022
Callahan MJ, Lipinski WJ, Bian F, Durham RA, Pack A, Walker LC (2001) Augmented senile plaque load in aged female β-amyloid precursor protein-transgenic mice. Am J Pathol 158:1173–1177. https://doi.org/10.1016/S0002-9440(10)64064-3
Cameron HA, Glover LR (2015) Adult neurogenesis: beyond learning and memory. Annu Rev Psychol 66:53–81. https://doi.org/10.1146/annurev-psych-010814-015006
Caselli RJ, Dueck AC, Osborne D, Sabbagh MN, Connor DJ, Ahern GL, Baxter LC, Rapcsak SZ, Shi J, Woodruff BK, Locke DE, Snyder CH, Alexander GE, Rademakers R, Reiman EM (2009) Longitudinal modeling of age-related memory decline and the APOE epsilon4 effect. N Engl J Med 361:255–263. https://doi.org/10.1056/NEJMoa0809437
Chang HM, Wu HC, Sun ZG, Lian F, Leung PCK (2019) Neurotrophins and glial cell line-derived neurotrophic factor in the ovary: physiological and pathophysiological implications. Hum Reprod Update 25(2):224–242. https://doi.org/10.1093/humupd/dmy047
Chen S, Nilsen J, Brinton RD (2006) Dose and temporal pattern of estrogen exposure determines neuroprotective outcome in hippocampal neurons: therapeutic implications. Endocrinology 147:5303–5313. https://doi.org/10.1210/en.2006-0495
Chen Q, Nakajima A, Choi SH, Xiong X, Sisodia SS, Tang YP (2007) Adult neurogenesis is functionally associated with AD-like neurodegeneration. Neurobiol Dis 29:316–326. https://doi.org/10.1016/j.nbd.2007.09.005
Chen Y, Durakoglugil MS, Xian X, Herz J (2010) ApoE4 reduces glutamate receptor function and synaptic plasticity by selectively impairing ApoE receptor recycling. Proc Natl Acad Sci USA 107:12011–12016. https://doi.org/10.1073/pnas.0914984107
Chhibber A, Woody SK, Rumi MK, Soares MJ, Zhao L (2017) Estrogen receptor β deficiency impairs BDNF–5-HT2A signaling in the hippocampus of female brain: a possible mechanism for menopausal depression. Psychoneuroendocrinology 82:107–116. https://doi.org/10.1016/j.psyneuen.2017.05.016
Correia SC, Santos RX, Cardoso S, Carvalho CS, Santos MR, Oliveira CI, Moreira P (2010) Effects of estrogen in the brain: is it a neuroprotective agent in Alzheimer’s disease? Curr Aging Sci 3:113–126. https://doi.org/10.2174/1874609811003020113
Craig MC, Murphy D (2010) Estrogen therapy and Alzheimer’s dementia. Ann N Y Acad Sci 1205:245–253. https://doi.org/10.1111/j.1749-6632.2010.05673.x
Craig MC, Fletcher PC, Daly EM, Rymer J, Brammer M, Giampietro V, Murphy DG (2008) Physiological variation in estradiol and brain function: a functional magnetic resonance imaging study of verbal memory across the follicular phase of the menstrual cycle. Horm Behav 53:503–508. https://doi.org/10.1016/j.yhbeh.2007.11.005
Crous-Bou M, Minguillon C, Gramunt N, Molinuevo JL (2017) Alzheimer’s disease prevention: from risk factors to early intervention. Alzheimer’s Res Therapy 9:71–80. https://doi.org/10.1186/s13195-017-0297-z
Dana P, Ghorbanian M (2018) Neurogenesis in the dentate gyrus of the hippocampus associated with sex hormone levels in female mice during different stages of the estrous cycle. J Cell Biol Histol 1:105–117. https://doi.org/10.15744/2638-082X.1.105
Deng W, Aimone JB, Gage FH (2010) New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? Nat Rev Neurosci 11(5):339–350. https://doi.org/10.1038/nrn2822
Denley MC, Gatford NJ, Sellers KJ, Srivastava DP (2018) Estradiol and the development of the cerebral cortex: an unexpected role? Front Neurosci 12:245–264. https://doi.org/10.3389/fnins.2018.00245
Dhandapani KM, Brann DW (2007) Role of astrocytes in estrogen-mediated neuroprotection. Exp Gerontol 42:70–75. https://doi.org/10.1016/j.exger.2006.06.032
Dias GP, Cocks G, do Nascimento Bevilaqua MC, Nardi AE, Thuret S (2016) Resveratrol: a potential hippocampal plasticity enhancer. Oxid Med Cell Longev 2016:9651236. https://doi.org/10.1155/2016/9651236
Dorostkar MM, Zou C, Blazquez-Llorca L, Herms J (2015) Analyzing dendritic spine pathology in Alzheimer’s disease: problems and opportunities. Acta Neuropathol 130:1–19. https://doi.org/10.1007/s00401-015-1449-5
Du X, Hill RA (2016) The potential of gonadal hormone signalling pathways as therapeutics for dementia. J Mol Neurosci 60(3):336–348. https://doi.org/10.1007/s1203
Duarte A, Hrynchak M, Gonçalves I, Quintela T, Santos C (2016) Sex hormone decline and amyloid β synthesis, transport and clearance in the brain. J Neuroendocrinol. https://doi.org/10.1111/jne.12432
Duarte-Guterman P, Lieblich SE, Chow C, Galea LA (2015a) Estradiol and GPER activation differentially affect cell proliferation but not GPER expression in the hippocampus of adult female rats. PLoS ONE 10(6):e0129880. https://doi.org/10.1371/journal.pone.0129880
Duarte-Guterman P, Yagi S, Chow C, Galea LA (2015b) Hippocampal learning, memory, and neurogenesis: effects of sex and estrogens across the lifespan in adults. Horm Behav 74:37–52. https://doi.org/10.1016/j.yhbeh.2015.05.024
Dubois B, Hampel H, Feldman HH, Scheltens P, Aisen P, Andrieu S, Bakardjian H, Benali H, Bertram L, Blennow K, Broich K, Cavedo E, Crutch S, Dartigues JF, Duyckaerts C, Epelbaum S, Frisoni GB, Gauthier S, Genthon R, Gouw AA, Habert MO, Holtzman DM, Kivipelto M, Lista S, Molinuevo JL, O’Bryant SE, Rabinovici GD, Rowe C, Salloway S, Schneider LS, Sperling R, Teichmann M, Carrillo MC, Cummings J, Jack CR Jr (2016) Preclinical Alzheimer’s disease: definition, natural history, and diagnostic criteria. Alzheimers Dement 12:292–323. https://doi.org/10.1016/j.jalz.2016.02.002
Elsabagh S, Hartley DE, File SE (2007) Cognitive function in late versus early postmenopausal stage. Maturitas 56:84–93. https://doi.org/10.1016/j.maturitas.2006.06.007
El-Sayed NS, Bayan Y (2015) Possible role of resveratrol targeting estradiol and neprilysin pathways in lipopolysaccharide model of Alzheimer disease. Adv Exp Med Biol 822:107–118. https://doi.org/10.1007/978-3-319-08927-0_12
Fahnestock M, Garzon D, Holsinger RM, Michalski B (2002) Neurotrophic factors and Alzheimer’s disease: are we focusing on the wrong molecule? J Neural Transm Suppl 1(62):241–252. https://doi.org/10.1007/978-3-7091-6139-5_22
Fan L, Zhao Z, Orr PT, Chambers CH, Lewis MC, Frick KM (2010) Estradiol-induced object memory consolidation in middle-aged female mice requires dorsal hippocampal extracellular signal-regulated kinase and phosphatidylinositol 3-kinase activation. J Neurosci 30:4390–4400. https://doi.org/10.1523/JNEUROSCI.4333-09.2010
Fester L, Prange-Kiel J, Zhou L, Blittersdorf BV, Bohm J, Jarry H, Schumacher M, Rune GM (2012) Estrogen-regulated synaptogenesis in the hippocampus: sexual dimorphism in vivo but not in vitro. J Steroid Biochem Mol Biol 131:24–29. https://doi.org/10.1016/j.jsbmb.2011.11.010
Franklin TB, Perrot-Sinal TS (2006) Sex and ovarian steroids modulate brain-derived neurotrophic factor (BDNF) protein levels in rat hippocampus under stressful and non-stressful conditions. Psychoneuroendocrinology 31(1):38–48. https://doi.org/10.1016/j.psyneuen.2005.05.008
Frick KM (2015) Molecular mechanisms underlying the memory-enhancing effects of estradiol. Horm Behav 74:4–18. https://doi.org/10.1016/j.yhbeh.2015.05.001
Galea LA (2008) Gonadal hormone modulation of neurogenesis in the dentate gyrus of adult male and female rodents. Brain Res Rev 57:332–341. https://doi.org/10.1016/j.brainresrev.2007.05.008
Galea LA, Spritzer MD, Barker JM, Pawluski JL (2006) Gonadal hormone modulation of hippocampal neurogenesis in the adult. Hippocampus 16:225–232. https://doi.org/10.1002/hipo.20154
Galea LA, Wainwright SR, Roes M, Duarte-Guterman P, Chow C, Hamson D (2013) Sex, hormones and neurogenesis in the hippocampus: hormonal modulation of neurogenesis and potential functional implications. J Neuroendocrinol 25:1039–1061. https://doi.org/10.1111/jne.12070
Gan L, Qiao S, Lan X, Chi L, Luo C, Lien L, Yan LQ, Liu R (2007) Neurogenic responses to amyloid-beta plaques in the brain of Alzheimer’s disease-like transgenic (pPDGF-APPSw, Ind) mice. Neurobiol Dis 29(1):71–80. https://doi.org/10.1016/j.nbd.2007.08.002
George S, Petit GH, Gouras GK, Brundin P, Olsson R (2013) Nonsteroidal selective androgen receptor modulators and selective estrogen receptor β agonists moderate cognitive deficits and amyloid-β levels in a mouse model of Alzheimer’s disease. ACS Chem Neurosci 4:1537–1548. https://doi.org/10.1021/cn400133s
Gibbs RB (1998) Levels of trkA and BDNF mRNA, but not NGF mRNA, fluctuate across the estrous cycle and increase in response to acute hormone replacement. Brain Res 787(2):259–268. https://doi.org/10.1016/S0006-8993(97)01511-4
Gibbs RB (1999) Treatment with estrogen and progesterone affects relative levels of brain-derived neurotrophic factor mRNA and protein in different regions of the adult rat brain. Brain Res 844:20–27. https://doi.org/10.1016/S0006-8993(99)01880-6
Gould E, Woolley CS, Frankfurt M, McEwen BS (1990) Gonadal steroids regulate dendritic spine density in hippocampal pyramidal cells in adulthood. J Neurosci 10:1286–1291. https://doi.org/10.1523/JNEUROSCI.10-04-01286.1990
Green PS, Bishop J, Simpkins JW (1997) 17α-Estradiol exerts neuroprotective effects on SK-N-SH cells. J Neurosci 17(2):511–515. https://doi.org/10.1523/JNEUROSCI.17-02-00511.1997
Grimm A, Lim YA, Mensah-Nyagan AG, Gotz J, Eckert A (2012) Alzheimer’s disease, oestrogen and mitochondria: an ambiguous relationship. Mol Neurobiol 46:151–160. https://doi.org/10.1007/s12035-012-8281-x
Guo JW, Guan PP, Ding WY, Wang SL, Huang XS, Wang ZY, Wang P (2017) Erythrocyte membrane-encapsulated celecoxib improves the cognitive decline of Alzheimer’s disease by concurrently inducing neurogenesis and reducing apoptosis in APP/PS1 transgenic mice. Biomaterials 145:106–127. https://doi.org/10.1016/j.biomaterials.2017.07.023
Han SM, Baig HS, Hammarlund M (2016) Mitochondria localize to injured axons to support regeneration. Neuron 92:1308–1323. https://doi.org/10.1016/j.neuron.2016.11.025
Haraguchi S, Sasahara K, Shikimi H, Honda S, Harada N, Tsutsui K (2012) Estradiol promotes purkinje dendritic growth, spinogenesis, and synaptogenesis during neonatal life by inducing the expression of BDNF. Cerebellum 11:416–417. https://doi.org/10.1007/s12311-011-0342-6
Hazell GG, Yao ST, Roper JA, Prossnitz ER, O’Carroll AM, Lolait SJ (2009) Localisation of GPR30, a novel G protein-coupled oestrogen receptor, suggests multiple functions in rodent brain and peripheral tissues. J Endocrinol 202:223–236. https://doi.org/10.1677/JOE-09-0066
Heberden C (2017) Sex steroids and neurogenesis. Biochem Pharmacol 141:56–62. https://doi.org/10.1016/j.bcp.2017.05.019
Henderson VW, John JAS, Hodis HN, McCleary CA, Stanczyk FZ, Shoupe D, Kono N, Dustin L, Allayee H, Mack WJ (2016) Cognitive effects of estradiol after menopause A randomized trial of the timing hypothesis. Neurology 87:699–708. https://doi.org/10.1212/WNL.0000000000002980
Herring A, Münster Y, Akkaya T, Moghaddam S, Deinsberger K, Meyer J, Zahel J, Sanchez-Mendoza E, Wang Y, Hermann DM (2016) Kallikrein-8 inhibition attenuates Alzheimer’s disease pathology in mice. Alzheimers Dement 12:1273–1287. https://doi.org/10.1016/j.jalz.2016.05.006
Hirata-Fukae C, Li HF, Hoe HS, Gray AJ, Minami SS, Hamada K, Niikura T, Hua F, Tsukagoshi-Nagai H, Horikoshi-Sakuraba Y, Mughal M, Rebeck GW, LaFerla FM, Mattson MP, Iwata N, Saido TC, Klein WL, Duff KE, Aisen PS, Matsuoka Y (2008) Females exhibit more extensive amyloid, but not tau, pathology in an Alzheimer transgenic model. Brain Res 1216:92–103. https://doi.org/10.1016/j.brainres.2008.03.079
Hoekstra JG, Hipp MJ, Montine TJ, Kennedy SR (2016) Mitochondrial DNA mutations increase in early stage Alzheimer disease and are inconsistent with oxidative damage. Ann Neurol 80:301–306. https://doi.org/10.1002/ana.24709
Hojo Y, Hattori TA, Enami T, Furukawa A, Suzuki K, Ishii HT, Mukai H, Morrison JH, Janssen WG, Kominami S, Harada N, Kimoto T, Kawato S (2004) Adult male rat hippocampus synthesizes estradiol from pregnenolone by cytochromes P45017α and P450 aromatase localized in neurons. Proc Natl Acad Sci USA 101(3):865–870. https://doi.org/10.1073/pnas.2630225100
Hojo Y, Higo S, Kawato S, Hatanaka Y, Ooishi Y, Murakami G, Ishii H, Komatsuzaki Y, Ogiue-Ikeda M, Mukai H, Kimoto T (2011) Hippocampal synthesis of sex steroids and corticosteroids: essential for modulation of synaptic plasticity. Front Endocrinol 2:43. https://doi.org/10.3389/fendo.2011.00043
Holder MK, Mong JA (2017) The role of ovarian hormones and the medial amygdala in sexual motivation. Curr Sex Health Rep 9(4):262–270
Hollands C, Bartolotti N, Lazarov O (2016) Alzheimer’s disease and hippocampal adult neurogenesis; exploring shared mechanisms. Front Neurosci 10:178. https://doi.org/10.3389/fnins.2016.00178
Hollands C, Tobin MK, Hsu M, Musaraca K, Yu TS, Mishra R, Kernie SG, Lazarov O (2017) Depletion of adult neurogenesis exacerbates cognitive deficits in Alzheimer’s disease by compromising hippocampal inhibition. Mol Neurodegener 12(1):64. https://doi.org/10.1186/s13024-017-0207-7
Ignar-Trowbridge DM, Pimentel M, Teng CT, Korach KS, McLachlan JA (1995) Cross talk between peptide growth factor and estrogen receptor signaling systems. Environ Health Perspect 7:35–38. https://doi.org/10.1289/ehp.95103s735
Imayoshi I, Sakamoto M, Ohtsuka T, Takao K, Miyakawa T, Yamaguchi M, Mori K, Ikeda T, Itohara S, Kageyama R (2008) Roles of continuous neurogenesis in the structural and functional integrity of the adult forebrain. Nat Neurosci 11(10):1153–1161. https://doi.org/10.1038/nn.2185
Inagaki T, Frankfurt M, Luine V (2012) Estrogen-induced memory enhancements are blocked by acute bisphenol A in adult female rats: role of dendritic spines. Endocrinology 153:3357–3367. https://doi.org/10.1210/en.2012-1121
Iughetti L, Lucaccioni L, Fugetto F, Predieri B, Berardi A, Ferrari F (2018) Brain-derived neurotrophic factor and epilepsy: a systematic review. Neuropeptides 72:23–29. https://doi.org/10.1016/j.npep.2018.09.005
Jin K, Peel AL, Mao XO, Xie L, Cottrell BA, Henshall DC, Greenberg DA (2003) Increased hippocampal neurogenesis in Alzheimer’s disease. Proc Natl Acad Sci USA 101(1):343–347. https://doi.org/10.1073/pnas.2634794100
Jin K, Xie L, Mao XO, Greenberg DA (2006) Alzheimer’s disease drugs promote neurogenesis. Brain Res 1085(1):183–188. https://doi.org/10.1016/j.brainres.2006.02.081
Kempermann G (2019) Environmental enrichment, new neurons and the neurobiology of individuality. Nat Rev Neurosci 20(4):235–245. https://doi.org/10.1038/s41583-019-0120-x
Kempermann G, Song H, Gage FH (2015) Neurogenesis in the adult hippocampus. Cold Spring Harb Perspect Biol 7(9):a018812. https://doi.org/10.1101/cshperspect.a018812
Keyvani K, Münster Y, Kurapati NK, Rubach S, Schonborn A, Kocakavuk E, Karout M, Hammesfahr P, Wang YC, Hermann DM, Teuber-Hanselmann S, Herring A (2018) Higher levels of kallikrein-8 in female brain may increase the risk for Alzheimer’s disease. Brain Pathol 28:947–964. https://doi.org/10.1111/bpa.12599
Khan MM, Wakade C, de Sevilla L, Brann DW (2014) Selective estrogen receptor modulators (SERMs) enhance neurogenesis and spine density following focal cerebral ischemia. J Steroid Biochem Mol Biol 146:38–47. https://doi.org/10.1016/j.jsbmb.2014.05.001
Kight KE, McCarthy MM (2017) Sex differences and estrogen regulation of BDNF gene expression, but not propeptide content, in the developing hippocampus. J Neurosci Res 95(1–2):345–354. https://doi.org/10.1002/jnr.23920
Kiss A, Delattre AM, Pereira SI, Carolino RG, Szawka RE, Anselmo-Franci JA, Zanata SM, Ferraz AC (2012) 17beta-estradiol replacement in young, adult and middle-aged female ovariectomized rats promotes improvement of spatial reference memory and an antidepressant effect and alters monoamines and BDNF levels in memory- and depression-related brain areas. Behav Brain Res 227(1):100–108. https://doi.org/10.1016/j.bbr.2011.10.047
Kodali M, Parihar VK, Hattiangady B, Mishra V, Shuai B, Shetty AK (2015) Resveratrol prevents age-related memory and mood dysfunction with increased hippocampal neurogenesis and microvasculature, and reduced glial activation. Sci Rep 5:8075. https://doi.org/10.1038/srep08075
Kong D, Yan Y, He XY, Yang H, Liang B, Wang J, He Y, Ding Y, Yu H (2019) Effects of resveratrol on the mechanisms of antioxidants and estrogen in Alzheimer’s disease. Biomed Res Int 2019:8983752. https://doi.org/10.1155/2019/8983752
Kretz O, Fester L, Wehrenberg U, Zhou L, Brauckmann S, Zhao S, Prange-Kiel J, Naumann T, Jarry H, Frotscher M, Rune GM (2004) Hippocampal synapses depend on hippocampal estrogen synthesis. J Neurosci 24:5913–5921. https://doi.org/10.1523/JNEUROSCI.5186-03.2004
Lazarov O, Mattson MP, Peterson DA, Pimplikar SW, Van Praag H (2010) When neurogenesis encounters aging and disease. Trends Neurosci 33(12):569–579. https://doi.org/10.1016/j.tins.2010.09.003
LeBlanc ES, Janowsky J, Chan BK, Nelson HD (2001) Hormone replacement therapy and cognition: systematic review and meta-analysis. JAMA 285:1489–1499. https://doi.org/10.1001/jama.285.11.1489
Lewis MC, Kerr KM, Orr PT, Frick KM (2008) Estradiol-induced enhancement of object memory consolidation involves NMDA receptors and protein kinase A in the dorsal hippocampus of female C57BL/6 mice. Behav Neurosci 122:716–721. https://doi.org/10.1037/0735-7044.122.3.716
Li R, Cui J, Shen Y (2014) Brain sex matters: estrogen in cognition and Alzheimer’s disease. Mol Cell Endocrinol 389:13–21. https://doi.org/10.1016/j.mce.2013.12.018
Li KX, Sun Q, Wei LL, Du GH, Huang X, Wang JK (2019a) ERα gene promoter methylation in cognitive function and quality of life of patients with Alzheimer disease. J Geriatr Psychiatry Neurol 32(4):221–228. https://doi.org/10.1177/0891988719835325
Li W, Li H, Wei H, Lu Y, Lei S, Zheng J, Lu H, Chen X, Liu Y, Zhang P (2019b) 17β-Estradiol treatment attenuates neurogenesis damage and improves behavior performance after ketamine exposure in neonatal rats. Front Cell Neurosci 13:251. https://doi.org/10.3389/fncel.2019.00251
Lim YA, Grimm A, Giese M, Mensah-Nyagan AG, Villafranca JE, Ittner LM, Eckert A, Gotz J (2011) Inhibition of the mitochondrial enzyme ABAD restores the amyloid-β-mediated deregulation of estradiol. PLoS ONE 6:e28887. https://doi.org/10.1371/journal.pone.0028887
Lindvall O, Kokaia Z (2010) Stem cells in human neurodegenerative disorders–time for clinical translation? J Clin Invest 120(1):29–40. https://doi.org/10.1172/JCI40543
Liu CC, Liu CC, Kanekiyo T, Xu H, Bu G (2013) Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol 9(2):106–118. https://doi.org/10.1038/nrneurol.2012.263
Lu Y, Sareddy GR, Wang J, Wang R, Li Y, Dong Y, Zhang Q, Liu J, O’Connor J, Xu J, Ratna KV, Brann D (2019) Neuron-derived estrogen regulates synaptic plasticity and memory. J Neurosci. https://doi.org/10.1523/JNEUROSCI.1970-18.2019
Luine V, Frankfurt M (2013) Interactions between estradiol, BDNF and dendritic spines in promoting memory. Neuroscience 239:34–45. https://doi.org/10.1016/j.neuroscience.2012.10.019
Ma DK, Marchetto MC, Guo JU, Ming GL, Gage FH, Song H (2010) Epigenetic choreographers of neurogenesis in the adult mammalian brain. Nat Neurosci 13(11):1338–1344. https://doi.org/10.1038/nn.2672
Mahmoud R, Wainwright SR, Galea LA (2016) Sex hormones and adult hippocampal neurogenesis: regulation, implications, and potential mechanisms. Front Neuroendocrinol 41:129–152. https://doi.org/10.1016/j.yfrne.2016.03.002
Malva J, Xapelli S, Baptista S, Valero J, Agasse F, Ferreira R, Silva A (2012) Multifaces of neuropeptide Y in the brain–neuroprotection, neurogenesis and neuroinflammation. Neuropeptides 46:299–308. https://doi.org/10.1016/j.npep.2012.09.001
McClure RE, Barha CK, Galea LA (2013) 17β-Estradiol, but not estrone, increases the survival and activation of new neurons in the hippocampus in response to spatial memory in adult female rats. Horm Behav 63:144–157. https://doi.org/10.1016/j.yhbeh.2012.09.011
Mehra RD, Sharma K, Nyakas C, Vij U (2005) Estrogen receptor alpha and beta immunoreactive neurons in normal adult and aged female rat hippocampus: a qualitative and quantitative study. Brain Res 1056:22–35. https://doi.org/10.1016/j.brainres.2005.06.073
Merlo S, Spampinato SF, Sortino MA (2017) Estrogen and Alzheimer’s disease: still an attractive topic despite disappointment from early clinical results. Eur J Pharmacol 817:51–58. https://doi.org/10.1016/j.ejphar.2017.05.059
Micheli F, Palermo R, Talora C, Ferretti E, Vacca A, Napolitano M (2016) Regulation of proapoptotic proteins Bak1 and p53 by miR-125b in an experimental model of Alzheimer’s disease: protective role of 17β-estradiol. Neurosci Lett 629:234–240. https://doi.org/10.1016/j.neulet.2016.05.049
Miller VM, Duckles SP (2008) Vascular actions of estrogens: functional implications. Pharmacol Rev 60:210–241. https://doi.org/10.1124/pr.107.08002
Milner TA, Ayoola K, Drake CT, Herrick SP, Tabori NE, McEwen BS, Warrier S, Alves SE (2005) Ultrastructural localization of estrogen receptor beta immunoreactivity in the rat hippocampal formation. J Comp Neurol 491:81–95. https://doi.org/10.1002/cne.20724
Ming GL, Song H (2011) Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron 70:687–702. https://doi.org/10.1016/j.neuron.2011.05.001
Monje ML, Mizumatsu S, Fike JR, Palmer TD (2002) Irradiation induces neural precursor-cell dysfunction. Nat Med 8:955–962. https://doi.org/10.1038/nm749
Morello M, Landel V, Lacassagne E, Baranger K, Annweiler C, Feron F, Millet P (2018) Vitamin D improves neurogenesis and cognition in a mouse model of Alzheimer’s disease. Mol Neurobiol 55:6463–6479. https://doi.org/10.1007/s12035-017-0839-1
Moreno-Jiménez EP, Flor-García M, Terreros-Roncal J, Rábano A, Cafini F, Pallas-Bazarra N, Ávila J, Llorens-Martín M (2019) Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer’s disease. Nat Med 25(4):554–560. https://doi.org/10.1038/s41591-019-0375-9
Mu Y, Gage FH (2011) Adult hippocampal neurogenesis and its role in Alzheimer’s disease. Mol Neurodegener 6:85. https://doi.org/10.1186/1750-1326-6-85
Mukherjee J, Cardarelli RA, Cantaut-Belarif Y, Deeb TZ, Srivastava DP, Tyagarajan SK, Pangalos MN, Triller A, Maguire J, Brandon NJ, Moss SJ (2017) Estradiol modulates the efficacy of synaptic inhibition by decreasing the dwell time of GABAA receptors at inhibitory synapses. Proc Natl Acad Sci USA 114:11763–11768. https://doi.org/10.1073/pnas.1705075114
Mulnard RA, Cotman CW, Kawas C, van Dyck CH, Sano M, Doody R, Koss E, Pfeiffer E, Jin S, Gamst A, Grundman M, Thomas R, Thal LJ (2000) Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial. Alzheimer’s disease cooperative study. JAMA 283:1007–1015. https://doi.org/10.1001/jama.283.8.1007
Murphy DD, Cole NB, Segal M (1998) Brain-derived neurotrophic factor mediates estradiol-induced dendritic spine formation in hippocampal neurons. Proc Natl Acad Sci USA 95:11412–11417. https://doi.org/10.1073/pnas.95.19.11412
Nakamura NH, McEwen BS (2005) Changes in interneuronal phenotypes regulated by estradiol in the adult rat hippocampus: a potential role for neuropeptide Y. Neuroscience 136:357–369. https://doi.org/10.1016/j.neuroscience.2005.07.056
Negah SS, Khooei A, Samini F, Gorji A (2017) Laminin-derived Ile-Lys-Val-ala-Val: a promising bioactive peptide in neural tissue engineering in traumatic brain injury. Cell Tissue Res 371(2):223–236. https://doi.org/10.1007/s00441-017-2717-6
Nilsen J, Chen S, Brinton RD (2002) Dual action of estrogen on glutamate-induced calcium signaling: mechanisms requiring interaction between estrogen receptors and src/mitogen activated protein kinase pathway. Brain Res 930:216–234. https://doi.org/10.1016/s0006-8993(02)02254-0
Numakawa T, Yokomaku D, Richards M, Hori H, Adachi N, Kunugi H (2010) Functional interactions between steroid hormones and neurotrophin BDNF. World J Biol Chem 1:133–143. https://doi.org/10.4331/wjbc.v1.i5.133
Nuttall J, Oteiza P (2012) Zinc and the ERK kinases in the developing brain. Neurotox Res 21:128–141. https://doi.org/10.1007/s12640-011-9291-6
Oberlander JG, Woolley CS (2016) 17β-Estradiol acutely potentiates glutamatergic synaptic transmission in the hippocampus through distinct mechanisms in males and females. J Neurosci 36:2677–2690. https://doi.org/10.1523/JNEUROSCI.4437-15.2016
O’Leime CS, Cryan JF, Nolan YM (2017) Nuclear deterrents: intrinsic regulators of IL-1β-induced effects on hippocampal neurogenesis. Brain Behav Immun 66:394–412. https://doi.org/10.1016/j.bbi.2017.07.153
Ormerod B, Lee TTY, Galea L (2003) Estradiol initially enhances but subsequently suppresses (via adrenal steroids) granule cell proliferation in the dentate gyrus of adult female rats. J Neurobiol 55:247–260. https://doi.org/10.1002/neu.10181
Pawluski JL, Brummelte S, Barha CK, Crozier TM, Galea LA (2009) Effects of steroid hormones on neurogenesis in the hippocampus of the adult female rodent during the estrous cycle, pregnancy, lactation and aging. Front Neuroendocrinol 30:343–357. https://doi.org/10.1016/j.yfrne.2009.03.007
Perez SE, Chen EY, Mufson EJ (2003) Distribution of estrogen receptor alpha and beta immunoreactive profiles in the postnatal rat brain. Dev Brain Res 145:117–139. https://doi.org/10.1016/S0165-3806(03)00223-2
Pfaff D, Keiner M (1973) Atlas of estradiol-concentrating cells in the central nervous system of the female rat. J Comp Neurol 151:121–158. https://doi.org/10.1002/cne.901510204
Pike CJ (2017) Sex and the development of Alzheimer’s disease. J Neurosci Res 95:671–680. https://doi.org/10.1002/jnr.23827
Pike CJ, Carroll JC, Rosario ER, Barron AM (2009) Protective actions of sex steroid hormones in Alzheimer’s disease. Front Neuroendocrinol 30(2):239–258. https://doi.org/10.1016/j.yfrne.2009.04.015
Plotnikov A, Zehorai E, Procaccia S, Seger R (2011) The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation. Biochim Biophys Acta 1813:1619–1633. https://doi.org/10.1016/j.bbamcr.2010.12.012
Polani PE (2000) Olfactory dysfunction in Alzheimer’s disease. Lancet 355:1015. https://doi.org/10.1016/S0140-6736(05)74756-5
Pooley AE, Luong M, Hussain A, Nathan BP (2015) Neurite outgrowth promoting effect of 17-β estradiol is mediated through estrogen receptor alpha in an olfactory epithelium culture. Brain Res 1624:19–27. https://doi.org/10.1016/j.brainres.2015.07.015
Prat A, Behrendt M, Marcinkiewicz E, Boridy S, Sairam RM, Seidah NG, Maysinger D (2011) A novel mouse model of Alzheimer’s disease with chronic estrogen deficiency leads to glial cell activation and hypertrophy. J Aging Res 2011:251517. https://doi.org/10.4061/2011/251517
Price RH, Handa RJ (2000) Expression of estrogen receptor-beta protein and mRNA in the cerebellum of the rat. Neurosci Lett 288:115–118. https://doi.org/10.1016/S0304-3940(00)01221-0
Prossnitz ER, Barton M (2011) The G-protein-coupled estrogen receptor GPER in health and disease. Nat Rev Endocrinol 7:715–726. https://doi.org/10.1038/nrendo.2011.122
Rapoport M, Dawson HN, Binder LI, Vitek MP, Ferreira A (2002) Tau is essential to β-amyloid-induced neurotoxicity. Proc Natl Acad Sci USA 99(9):6364–6369. https://doi.org/10.1073/pnas.092136199
Ridler C (2018) Exercise wards off Alzheimer disease by boosting neurogenesis and neuroprotective factors. Nat Rev Neurol 14(11):632. https://doi.org/10.1038/s41582-018-0085-9
Rivera C, Voipio J, Kaila K (2005) Two developmental switches in GABAergic signalling: the K+-Cl-cotransporter KCC2 and carbonic anhydrase CAVII. J Physiol 562:27–36. https://doi.org/10.1113/jphysiol.2004.077495
Rodriguez JJ, Verkhratsky A (2011) Neurogenesis in Alzheimer’s disease. J Anat 219:78–89. https://doi.org/10.1111/j.1469-7580.2011.01343.x
Ruiz-Palmero I, Hernando M, Garcia-Segura LM, Arevalo MA (2013) G protein-coupled estrogen receptor is required for the neuritogenic mechanism of 17β-estradiol in developing hippocampal neurons. Mol Cell Endocrinol 372:105–115. https://doi.org/10.1016/j.mce.2013.03.018
Ryan J, Carrière I, Carcaillon L, Dartigues JF, Auriacombe S, Rouaud O, Berr C, Ritchie K, Scarabin PY, Ancelin ML (2014) Estrogen receptor polymorphisms and incident dementia: the prospective 3C study. Alzheimers Dement 10(1):27–35. https://doi.org/10.1016/j.jalz.2012.12.008
Sachs M, Pape HC, Speckmann EJ, Gorji A (2007) The effect of estrogen and progesterone on spreading depression in rat neocortical tissues. Neurobiol Dis 25:27–34. https://doi.org/10.1016/j.nbd.2006.08.013
Sager T, Kashon ML, Krajnak K (2018) Estrogen and environmental enrichment differentially affect neurogenesis, dendritic spine immunolabeling and synaptogenesis in the hippocampus of young and reproductively senescent female rats. Neuroendocrinology 106:252–263. https://doi.org/10.1159/000479699
Sailor KA, Ming GL, Song H (2006) Neurogenesis as a potential therapeutic strategy for neurodegenerative diseases. Expert Opin Biol Ther 6:879–890. https://doi.org/10.1517/14712598.6.9.879
Sawai T, Bernier F, Fukushima T, Hashimoto T, Ogura H, Nishizawa Y (2002) Estrogen induces a rapid increase of calcium-calmodulin-dependent protein kinase II activity in the hippocampus. Brain Res 950:308–311. https://doi.org/10.1016/s0006-8993(02)03186-4
Sawe N, Steinberg G, Zhao H (2008) Dual roles of the MAPK/ERK1/2 cell signaling pathway after stroke. J Neurosci Res 86:1659–1669. https://doi.org/10.1002/jnr.21604
Scharfman HE, MacLusky NJ (2006) Estrogen and brain-derived neurotrophic factor (BDNF) in hippocampus: complexity of steroid hormone-growth factor interactions in the adult CNS. Front Neuroendocrinol 27:415–435. https://doi.org/10.1016/j.yfrne.2006.09.004
Scharfman HE, MacLusky NJ (2008) Estrogen–growth factor interactions and their contributions to neurological disorders. Headache 48:S77–S89. https://doi.org/10.1111/j.1526-4610.2008.01200.x
Scharfman HE, Mercurio TC, Goodman JH, Wilson MA, MacLusky NJ (2003) Hippocampal excitability increases during the estrous cycle in the rat: a potential role for brain-derived neurotrophic factor. J Neurosci 23:11641–11652. https://doi.org/10.1523/JNEUROSCI.23-37-11641.2003
Scharfman H, Goodman J, Macleod A, Phani S, Antonelli C, Croll S (2005) Increased neurogenesis and the ectopic granule cells after intrahippocampal BDNF infusion in adult rats. Exp Neurol 192:348–356. https://doi.org/10.1016/j.expneurol.2004.11.016
Seo SY, Moon JY, Kang SY, Kwon OS, Kwon S, Bang SK, Kim SP, Choi KH, Ryu Y (2018) An estradiol-independent BDNF-NPY cascade is involved in the antidepressant effect of mechanical acupuncture instruments in ovariectomized rats. Sci Rep 8:5849. https://doi.org/10.1038/s41598-018-23824-2
Sha S, Hong J, Qu WJ, Lu ZH, Li L, Yu WF, Chen L (2015) Sex-related neurogenesis decrease in hippocampal dentate gyrus with depressive-like behaviors in sigma-1 receptor knockout mice. Eur Neuropsychopharmacol 25:1275–1286. https://doi.org/10.1016/j.euroneuro.2015.04.021
Sharma K, Mehra RD, Dhar P, Vij U (2007) Chronic exposure to estrogen and tamoxifen regulates synaptophysin and phosphorylated cAMP response element-binding (CREB) protein expression in CA1 of ovariectomized rat hippocampus. Brain Res 1132:10–19. https://doi.org/10.1016/j.brainres.2006.11.027
Shohayeb B, Diab M, Ahmed M, Ng DCH (2018) Factors that influence adult neurogenesis as potential therapy. Transl Neurodegener 7:4. https://doi.org/10.1186/s40035-018-0109-9
Shughrue PJ, Merchenthaler I (2001) Distribution of estrogen receptor beta immunoreactivity in the rat central nervous system. J Comp Neurol 436:64–81. https://doi.org/10.1002/cne.1054
Simpkins JW, Singh M (2008) More than a decade of estrogen neuroprotection. Alzheimers Dement 4:S131–S136. https://doi.org/10.1016/j.jalz.2007.10.009
Singh M, Meyer EM, Simpkins JW (1995) The effect of ovariectomy and estradiol replacement on brain-derived neurotrophic factor messenger ribonucleic acid expression in cortical and hippocampal brain regions of female Sprague-Dawley rats. Endocrinology 136:2320–2324. https://doi.org/10.1210/endo.136.5.7720680
Sohrabji F, Miranda R, Toran-Allerand CD (1995) Identification of a putative estrogen response element in the gene encoding brain-derived neurotrophic factor. Proc Natl Acad Sci USA 92:11110–11114. https://doi.org/10.1073/pnas.92.24.11110
Solum DT, Handa RJ (2002) Estrogen regulates the development of brain-derived neurotrophic factor mRNA and protein in the rat hippocampus. J Neurosci 22:2650–2659. https://doi.org/10.1523/JNEUROSCI.22-07-02650.2002
Sopova K, Gatsiou K, Stellos K, Laske C (2014) Dysregulation of neurotrophic and haematopoietic growth factors in Alzheimer’s disease: from pathophysiology to novel treatment strategies. Curr Alzheimer Res 11:27–39. https://doi.org/10.2174/1567205010666131120100743
Sorrells SF, Paredes MF, Cebrian-Silla A, Sandoval K, Qi D, Kelley KW, James D, Mayer S, Chang J, Auguste KI, Chang EF, Gutierrez AJ, Kriegstein AR, Mathern GW, Oldham MC, Huang EJ, Garcia-Verdugo JM, Yang Z, Alvarez-Buylla A (2018) Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults. Nature 555(7696):377–381. https://doi.org/10.1038/nature25975
Spalding KL, Bergmann O, Alkass K, Bernard S, Salehpour M, Huttner HB, Bostrom E, Westerlund I, Vial C, Buchholz BA, Possnert G, Mash DC, Druid H, Frisen J (2013) Dynamics of hippocampal neurogenesis in adult humans. Cell 153(6):1219–1227. https://doi.org/10.1016/j.cell.2013.05.002
Stancel GM, Gardner RM, Kirkland JL, Lin TH, Lingham RB, Loose-Mitchell DS, Mukku VR, Orengo CA, Verner G (1987) Interactions between estrogen and EGF in uterine growth and function. Adv Exp Med Biol 230:99–118. https://doi.org/10.1007/978-1-4684-1297-0_6
Starkov AA (2008) The role of mitochondria in reactive oxygen species metabolism and signaling. Ann N Y Acad Sci 1147:37–52. https://doi.org/10.1196/annals.1427.015
Struble RG, Nathan BP, Cady C, Cheng X, McAsey M (2007) Estradiol regulation of astroglia and apolipoprotein E: an important role in neuronal regeneration. Exp Gerontol 42:54–63. https://doi.org/10.1016/j.exger.2006.05.013
Tanapat P, Hastings NB, Reeves AJ, Gould E (1999) Estrogen stimulates a transient increase in the number of new neurons in the dentate gyrus of the adult female rat. J Neurosci 19:5792–5801. https://doi.org/10.1523/JNEUROSCI.19-14-05792.1999
Tanapat P, Hastings NB, Gould E (2005) Ovarian steroids influence cell proliferation in the dentate gyrus of the adult female rat in a dose-and time-dependent manner. J Comp Neurol 481:252–265. https://doi.org/10.1002/cne.20385
Tang SS, Ren Y, Ren XQ, Cao JR, Hong H, Ji H, Hu QH (2019) ERα and/or ERβ activation ameliorates cognitive impairment, neurogenesis and apoptosis in type 2 diabetes mellitus mice. Exp Neurol 311:33–43. https://doi.org/10.1016/j.expneurol.2018.09.002
Teixeira CM, Pallas-Bazarra N, Bolos M, Terreros-Roncal J, Avila J, Llorens-Martin M (2018) Untold new beginnings: adult hippocampal neurogenesis and Alzheimer’s disease. J Alzheimers Dis 64:S497–S505. https://doi.org/10.3233/JAD-179918
Tensaouti Y, Stephanz EP, Yu TS, Kernie SG (2018) ApoE regulates the development of adult newborn hippocampal neurons. eNeuro 5(4):1–45. https://doi.org/10.1523/ENEURO.0155-18.2018
Tiwari SK, Agarwal S, Seth B, Yadav A, Nair S, Bhatnagar P, Karmakar M, Kumari M, Chauhan LK, Patel DK, Srivastava V, Singh D, Gupta SK, Tripathi A, Chaturvedi RK, Gupta KC (2014) Curcumin-loaded nanoparticles potently induce adult neurogenesis and reverse cognitive deficits in Alzheimer’s disease model via canonical Wnt/β-catenin pathway. ACS Nano 8(1):76–103. https://doi.org/10.1021/nn405077y
Toran-Allerand CD (2004) Minireview: a plethora of estrogen receptors in the brain: where will it end? Endocrinology 145:1069–1074. https://doi.org/10.1210/en.2003-1462
Trivino-Paredes J, Patten AR, Gil-Mohapel J, Christie BR (2016) The effects of hormones and physical exercise on hippocampal structural plasticity. Front Neuroendocrinol 41:23–43. https://doi.org/10.1016/j.yfrne.2016.03.001
Tschiffely AE, Schuh RA, Prokai-Tatrai K, Ottinger MA, Prokai L (2018) An exploratory investigation of brain-selective estrogen treatment in males using a mouse model of Alzheimer’s disease. Horm Behav 98:16–21. https://doi.org/10.1016/j.yhbeh.2017.11.015
Tuscher JJ, Luine V, Frankfurt M, Frick KM (2016) Estradiol-mediated spine changes in the dorsal hippocampus and medial prefrontal cortex of ovariectomized female mice depend on ERK and mTOR activation in the dorsal hippocampus. J Neurosci 36(5):1483–1489. https://doi.org/10.1523/JNEUROSCI.3135-15.2016
Vaucher E, Reymond I, Najaffe R, Kar S, Quirion R, Miller MM, Franklin KB (2002) Estrogen effects on object memory and cholinergic receptors in young and old female mice. Neurobiol Aging 23:87–95. https://doi.org/10.1016/S0197-4580(01)00250-0
Vezzani A, Sperk G, Colmers WF (1999) Neuropeptide Y: emerging evidence for a functional role in seizure modulation. Trends Neurosci 22:25–30. https://doi.org/10.1016/S0166-2236(98)01284-3
Von Schassen C, Fester L, Prange-Kiel J, Lohse C, Huber C, Bottner M, Rune G (2006) Oestrogen synthesis in the hippocampus: role in axon outgrowth. J Neuroendocrinol 18:847–856. https://doi.org/10.1111/j.1365-2826.2006.01484.x
Wallace M, Luine V, Arellanos A, Frankfurt M (2006) Ovariectomized rats show decreased recognition memory and spine density in the hippocampus and prefrontal cortex. Brain Res 1126:176–182. https://doi.org/10.1016/j.brainres.2006.07.064
Wang J, Tanila H, Puolivali J, Kadish I, van Groen T (2003) Gender differences in the amount and deposition of amyloidβ in APPswe and PS1 double transgenic mice. Neurobiol Dis 14:318–327. https://doi.org/10.1016/j.nbd.2003.08.009
Wang S, Ren P, Li X, Guan Y, Zhang YA (2011) 17β-estradiol protects dopaminergic neurons in organotypic slice of mesencephalon by MAPK-mediated activation of anti-apoptosis gene BCL2. J Mol Neurosci 45:236–245. https://doi.org/10.1007/s12031-011-9500-z
Wang C, Jie C, Dai X (2014) Possible roles of astrocytes in estrogen neuroprotection during cerebral ischemia. Rev Neurosci 25(2):255–268. https://doi.org/10.1515/revneuro-2013-0055
Wang X, Ma S, Yang B, Huang T, Meng N, Xu L, Xing Q, Zhang Y, Zhang K, Li Q, Zhang T, Wu J, Yang GL, Guan F, Wang J (2017) Resveratrol promotes hUC-MSCs engraftment and neural repair in a mouse model of Alzheimer’s disease. Behav Brain Res 339:297–304. https://doi.org/10.1016/j.bbr.2017.10.032
Wharton W, Gleason CE, Lorenze KR, Markgraf TS, Ries ML, Carlsson CM, Asthana S (2009) Potential role of estrogen in the pathobiology and prevention of Alzheimer’s disease. Am J Transl Res 1:131–147
Wide JK, Hanratty K, Ting J, Galea LA (2004) High level estradiol impairs and low level estradiol facilitates non-spatial working memory. Behav Brain Res 155(1):45–53. https://doi.org/10.1016/j.bbr.2004.04.001
Winblad B, Amouyel P, Andrieu S, Ballard C, Brayne C, Brodaty H, Cedazo-Minguez A, Dubois B, Edvardsson D, Feldman H, Fratiglioni L, Frisoni GB, Gauthier S, Georges J, Graff C, Iqbal K, Jessen F, Johansson G, Jonsson L, Kivipelto M, Knapp M, Mangialasche F, Melis R, Nordberg A, Rikkert MO, Qiu C, Sakmar TP, Scheltens P, Schneider LS, Sperling R, Tjernberg LO, Waldemar G, Wimo A, Zetterberg H (2016) Defeating Alzheimer’s disease and other dementias: a priority for European science and society. Lancet Neurol 15:455–532. https://doi.org/10.1016/S1474-4422(16)00062-4
Woolley CS, McEwen BS (1992) Estradiol mediates fluctuation in hippocampal synapse density during the estrous cycle in the adult rat. J Neurosci 12:2549–2554. https://doi.org/10.1523/JNEUROSCI.12-07-02549.1992
Wu TW, Wang JM, Chen S, Brinton RD (2005) 17β-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 135(1):59–72. https://doi.org/10.1016/j.neuroscience.2004.12.027
Wu SY, Chen YW, Tsai SF, Wu SN, Shih YH, Jiang-Shieh YF, Yang TT, Kuo YM (2016) Estrogen ameliorates microglial activation by inhibiting the Kir2.1 inward-rectifier K(+) channel. Sci Rep 6:22864. https://doi.org/10.1038/srep22864
Yaffe K, Haan M, Byers A, Tangen C, Kuller L (2000a) Estrogen use, APOE, and cognitive decline: evidence of gene-environment interaction. Neurology 54:1949–1954. https://doi.org/10.1212/WNL.54.10.1949
Yaffe K, Lui LY, Grady D, Cauley J, Kramer J, Cummings SR (2000b) Cognitive decline in women in relation to non-protein-bound oestradiol concentrations. Lancet 356:708–712. https://doi.org/10.1016/S0140-6736(00)02628-3
Yang ZD, Yu J, Zhang Q (2013) Effects of raloxifene on cognition, mental health, sleep and sexual function in menopausal women: a systematic review of randomized controlled trials. Maturitas 75:341–348. https://doi.org/10.1016/j.maturitas.2013.05.010
Ye M, Chung HS, An YH, Lim SJ, Choi W, Yu AR, Kim JS, Kang M, Cho S, Shim I, Bae H (2016) Standardized herbal formula PM012 decreases cognitive impairment and promotes neurogenesis in the 3xTg AD mouse model of Alzheimer’s disease. Mol Neurobiol 53(8):5401–5412. https://doi.org/10.1007/s12035-015-9458-x
Yi H, Bao X, Tang X, Fan X, Xu H (2016) Estrogen modulation of calretinin and BDNF expression in midbrain dopaminergic neurons of ovariectomised mice. J Chem Neuroanat 77:60–67. https://doi.org/10.1016/j.jchemneu.2016.05.005
Yildirim M, Janssen WG, Lou WW, Akama KT, McEwen BS, Milner TA, Morrison JH (2011) Effects of estrogen and aging on the synaptic distribution of phosphorylated Akt-immunoreactivity in the CA1 region of the female rat hippocampus. Brain Res 1379:98–108. https://doi.org/10.1016/j.brainres.2010.07.053
Yue X, Lu M, Lancaster T, Cao P, Honda SI, Staufenbiel M, Harada N, Zhong Z, Shen Y, Li R (2005) Brain estrogen deficiency accelerates Aβ plaque formation in an Alzheimer’s disease animal model. Proc Natl Acad Sci USA 102:19198–19203. https://doi.org/10.1073/pnas.0505203102
Zadran S, Qin Q, Bi X, Zadran H, Kim Y, Foy MR, Thompson R, Baudry M (2009) 17-β-estradiol increases neuronal excitability through MAP kinase-induced calpain activation. Proc Natl Acad Sci USA 106:21936–21941. https://doi.org/10.1073/pnas.0912558106
Zhao L, Brinton RD (2007) Estrogen receptor α and β differentially regulate intracellular Ca2+ dynamics leading to ERK phosphorylation and estrogen neuroprotection in hippocampal neurons. Brain Res 1172:48–59. https://doi.org/10.1016/j.brainres.2007.06.092
Zhao L, Jin C, Mao Z, Gopinathan MB, Rehder K, Brinton RD (2007) Design, synthesis, and estrogenic activity of a novel estrogen receptor modulator a hybrid structure of 17β-estradiol and vitamin E in hippocampal neurons. J Med Chem 50:4471–4481. https://doi.org/10.1021/jm070546x
Zheng JY, Liang KS, Wang XJ, Zhou XY, Sun J, Zhou SN (2017) Chronic estradiol administration during the early stage of Alzheimer’s disease pathology rescues adult hippocampal neurogenesis and ameliorates cognitive deficits in Aβ1–42 Mice. Mol Neurobiol 54:7656–7669. https://doi.org/10.1007/s12035-016-0181-z
Acknowledgements
We thank Ali Jahanbazi Jahan-Abad for his assistance in computer-aided design of figures.
Funding
This study was supported by the Iran National Science Foundation (INSF), National Institute for Medical Research (NIMAD; 964650), and the German Academic Exchange Service (DAAD; 57348208 and 57403633) to AG.
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SSN, VH, and HRM conceived the project, carried out analysis of previous topics, and wrote the preliminary draft. AG contributed to the final preparation of the manuscript and supervised the project. All authors contributed to the final draft of manuscript.
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Sahab-Negah, S., Hajali, V., Moradi, H.R. et al. The Impact of Estradiol on Neurogenesis and Cognitive Functions in Alzheimer’s Disease. Cell Mol Neurobiol 40, 283–299 (2020). https://doi.org/10.1007/s10571-019-00733-0
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DOI: https://doi.org/10.1007/s10571-019-00733-0