The Impact of Estradiol on Neurogenesis and Cognitive Functions in Alzheimer’s Disease

  • Sajad Sahab-Negah
  • Vahid Hajali
  • Hamid Reza Moradi
  • Ali GorjiEmail author
Review Paper


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.


Neurodegeneration Dementia Hormone Neurogenesis Cell therapy Brain 



We thank Ali Jahanbazi Jahan-Abad for his assistance in computer-aided design of figures.

Author Contributions

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.


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.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interests.

Ethical Approval

The manuscript is a review article.


  1. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  2. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  3. 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. CrossRefPubMedGoogle Scholar
  4. Altman J, Das GD (1965) Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol 124(3):319–335CrossRefPubMedGoogle Scholar
  5. Amakiri N, Kubosumi A, Tran J, Reddy PH (2019) Amyloid beta and microRNAs in Alzheimer’s disease. Front Neurosci 13:430. CrossRefPubMedPubMedCentralGoogle Scholar
  6. Anastasio TJ (2013) Exploring the contribution of estrogen to amyloid-Beta regulation: a novel multifactorial computational modeling approach. Front Pharmacol 4:16. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  8. Azcoitia I, Yague J, Garcia-Segura LM (2011) Estradiol synthesis within the human brain. Neuroscience 191:139–147. CrossRefPubMedGoogle Scholar
  9. 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. CrossRefPubMedGoogle Scholar
  10. 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. CrossRefPubMedGoogle Scholar
  11. Barron AM, Pike CJ (2012) Sex hormones, aging, and Alzheimer’s disease. Front Biosci 4:976–997Google Scholar
  12. 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. CrossRefPubMedGoogle Scholar
  13. 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. CrossRefPubMedGoogle Scholar
  14. 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. CrossRefPubMedGoogle Scholar
  15. 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. CrossRefPubMedGoogle Scholar
  16. 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. CrossRefPubMedGoogle Scholar
  17. Blaustein JD (1992) Cytoplasmic estrogen receptors in rat brain: immunocytochemical evidence using three antibodies with distinct epitopes. Endocrinology 131:1336–1342. CrossRefPubMedGoogle Scholar
  18. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 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. CrossRefPubMedGoogle Scholar
  20. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 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. CrossRefPubMedGoogle Scholar
  22. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  23. Briz V, Baudry M (2014) Estrogen regulates protein synthesis and actin polymerization in hippocampal neurons through different molecular mechanisms. Front Endocrinol 5:22. CrossRefGoogle Scholar
  24. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  25. Cameron HA, Glover LR (2015) Adult neurogenesis: beyond learning and memory. Annu Rev Psychol 66:53–81. CrossRefPubMedGoogle Scholar
  26. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  27. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  28. 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. CrossRefPubMedGoogle Scholar
  29. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  30. 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. CrossRefPubMedGoogle Scholar
  31. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  32. 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. CrossRefPubMedGoogle Scholar
  33. Craig MC, Murphy D (2010) Estrogen therapy and Alzheimer’s dementia. Ann N Y Acad Sci 1205:245–253. CrossRefPubMedGoogle Scholar
  34. 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. CrossRefPubMedGoogle Scholar
  35. 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. CrossRefGoogle Scholar
  36. 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. CrossRefGoogle Scholar
  37. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  38. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  39. Dhandapani KM, Brann DW (2007) Role of astrocytes in estrogen-mediated neuroprotection. Exp Gerontol 42:70–75. CrossRefPubMedGoogle Scholar
  40. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  41. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  42. Du X, Hill RA (2016) The potential of gonadal hormone signalling pathways as therapeutics for dementia. J Mol Neurosci 60(3):336–348. CrossRefPubMedGoogle Scholar
  43. 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. CrossRefPubMedGoogle Scholar
  44. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  45. 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. CrossRefPubMedGoogle Scholar
  46. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  47. Elsabagh S, Hartley DE, File SE (2007) Cognitive function in late versus early postmenopausal stage. Maturitas 56:84–93. CrossRefPubMedGoogle Scholar
  48. 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. CrossRefPubMedGoogle Scholar
  49. 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. CrossRefGoogle Scholar
  50. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  51. 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. CrossRefPubMedGoogle Scholar
  52. 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. CrossRefPubMedGoogle Scholar
  53. Frick KM (2015) Molecular mechanisms underlying the memory-enhancing effects of estradiol. Horm Behav 74:4–18. CrossRefPubMedPubMedCentralGoogle Scholar
  54. Galea LA (2008) Gonadal hormone modulation of neurogenesis in the dentate gyrus of adult male and female rodents. Brain Res Rev 57:332–341. CrossRefPubMedGoogle Scholar
  55. Galea LA, Spritzer MD, Barker JM, Pawluski JL (2006) Gonadal hormone modulation of hippocampal neurogenesis in the adult. Hippocampus 16:225–232. CrossRefPubMedGoogle Scholar
  56. 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. CrossRefPubMedGoogle Scholar
  57. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  58. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  59. 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. CrossRefPubMedGoogle Scholar
  60. 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. CrossRefPubMedGoogle Scholar
  61. 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. CrossRefPubMedGoogle Scholar
  62. Green PS, Bishop J, Simpkins JW (1997) 17α-Estradiol exerts neuroprotective effects on SK-N-SH cells. J Neurosci 17(2):511–515. CrossRefPubMedGoogle Scholar
  63. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  64. 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. CrossRefPubMedGoogle Scholar
  65. Han SM, Baig HS, Hammarlund M (2016) Mitochondria localize to injured axons to support regeneration. Neuron 92:1308–1323. CrossRefPubMedPubMedCentralGoogle Scholar
  66. 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. CrossRefPubMedGoogle Scholar
  67. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  68. Heberden C (2017) Sex steroids and neurogenesis. Biochem Pharmacol 141:56–62. CrossRefPubMedGoogle Scholar
  69. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  70. 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. CrossRefPubMedGoogle Scholar
  71. 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. CrossRefPubMedGoogle Scholar
  72. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  73. 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. CrossRefPubMedGoogle Scholar
  74. 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. CrossRefGoogle Scholar
  75. Holder MK, Mong JA (2017) The role of ovarian hormones and the medial amygdala in sexual motivation. Curr Sex Health Rep 9(4):262–270CrossRefPubMedPubMedCentralGoogle Scholar
  76. Hollands C, Bartolotti N, Lazarov O (2016) Alzheimer’s disease and hippocampal adult neurogenesis; exploring shared mechanisms. Front Neurosci 10:178. CrossRefPubMedPubMedCentralGoogle Scholar
  77. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  78. 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. CrossRefGoogle Scholar
  79. 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. CrossRefPubMedGoogle Scholar
  80. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  81. 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. CrossRefPubMedGoogle Scholar
  82. 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. CrossRefPubMedGoogle Scholar
  83. Jin K, Xie L, Mao XO, Greenberg DA (2006) Alzheimer’s disease drugs promote neurogenesis. Brain Res 1085(1):183–188. CrossRefPubMedGoogle Scholar
  84. Kempermann G (2019) Environmental enrichment, new neurons and the neurobiology of individuality. Nat Rev Neurosci 20(4):235–245. CrossRefPubMedGoogle Scholar
  85. Kempermann G, Song H, Gage FH (2015) Neurogenesis in the adult hippocampus. Cold Spring Harb Perspect Biol 7(9):a018812. CrossRefPubMedPubMedCentralGoogle Scholar
  86. 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. CrossRefPubMedGoogle Scholar
  87. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  88. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  89. 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. CrossRefPubMedGoogle Scholar
  90. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  91. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  92. 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. CrossRefPubMedGoogle Scholar
  93. Lazarov O, Mattson MP, Peterson DA, Pimplikar SW, Van Praag H (2010) When neurogenesis encounters aging and disease. Trends Neurosci 33(12):569–579. CrossRefPubMedPubMedCentralGoogle Scholar
  94. LeBlanc ES, Janowsky J, Chan BK, Nelson HD (2001) Hormone replacement therapy and cognition: systematic review and meta-analysis. JAMA 285:1489–1499. CrossRefPubMedGoogle Scholar
  95. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  96. Li R, Cui J, Shen Y (2014) Brain sex matters: estrogen in cognition and Alzheimer’s disease. Mol Cell Endocrinol 389:13–21. CrossRefPubMedPubMedCentralGoogle Scholar
  97. 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. CrossRefPubMedGoogle Scholar
  98. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  99. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  100. Lindvall O, Kokaia Z (2010) Stem cells in human neurodegenerative disorders–time for clinical translation? J Clin Invest 120(1):29–40. CrossRefPubMedPubMedCentralGoogle Scholar
  101. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  102. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  103. Luine V, Frankfurt M (2013) Interactions between estradiol, BDNF and dendritic spines in promoting memory. Neuroscience 239:34–45. CrossRefPubMedGoogle Scholar
  104. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  105. Mahmoud R, Wainwright SR, Galea LA (2016) Sex hormones and adult hippocampal neurogenesis: regulation, implications, and potential mechanisms. Front Neuroendocrinol 41:129–152. CrossRefPubMedGoogle Scholar
  106. 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. CrossRefPubMedGoogle Scholar
  107. 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. CrossRefPubMedGoogle Scholar
  108. 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. CrossRefPubMedGoogle Scholar
  109. 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. CrossRefPubMedGoogle Scholar
  110. 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. CrossRefPubMedGoogle Scholar
  111. Miller VM, Duckles SP (2008) Vascular actions of estrogens: functional implications. Pharmacol Rev 60:210–241. CrossRefPubMedPubMedCentralGoogle Scholar
  112. 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. CrossRefPubMedGoogle Scholar
  113. Ming GL, Song H (2011) Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron 70:687–702. CrossRefPubMedPubMedCentralGoogle Scholar
  114. Monje ML, Mizumatsu S, Fike JR, Palmer TD (2002) Irradiation induces neural precursor-cell dysfunction. Nat Med 8:955–962. CrossRefPubMedGoogle Scholar
  115. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  116. 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. CrossRefPubMedGoogle Scholar
  117. Mu Y, Gage FH (2011) Adult hippocampal neurogenesis and its role in Alzheimer’s disease. Mol Neurodegener 6:85. CrossRefPubMedPubMedCentralGoogle Scholar
  118. 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. CrossRefPubMedGoogle Scholar
  119. 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. CrossRefPubMedGoogle Scholar
  120. 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. CrossRefPubMedGoogle Scholar
  121. 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. CrossRefPubMedGoogle Scholar
  122. 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. CrossRefGoogle Scholar
  123. 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. CrossRefPubMedGoogle Scholar
  124. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  125. Nuttall J, Oteiza P (2012) Zinc and the ERK kinases in the developing brain. Neurotox Res 21:128–141. CrossRefPubMedGoogle Scholar
  126. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  127. 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. CrossRefPubMedGoogle Scholar
  128. 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. CrossRefPubMedGoogle Scholar
  129. 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. CrossRefPubMedGoogle Scholar
  130. 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. CrossRefGoogle Scholar
  131. 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. CrossRefPubMedGoogle Scholar
  132. Pike CJ (2017) Sex and the development of Alzheimer’s disease. J Neurosci Res 95:671–680. CrossRefPubMedPubMedCentralGoogle Scholar
  133. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  134. 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. CrossRefPubMedGoogle Scholar
  135. Polani PE (2000) Olfactory dysfunction in Alzheimer’s disease. Lancet 355:1015. CrossRefPubMedGoogle Scholar
  136. 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. CrossRefPubMedGoogle Scholar
  137. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  138. Price RH, Handa RJ (2000) Expression of estrogen receptor-beta protein and mRNA in the cerebellum of the rat. Neurosci Lett 288:115–118. CrossRefPubMedGoogle Scholar
  139. Prossnitz ER, Barton M (2011) The G-protein-coupled estrogen receptor GPER in health and disease. Nat Rev Endocrinol 7:715–726. CrossRefPubMedPubMedCentralGoogle Scholar
  140. 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. CrossRefPubMedGoogle Scholar
  141. Ridler C (2018) Exercise wards off Alzheimer disease by boosting neurogenesis and neuroprotective factors. Nat Rev Neurol 14(11):632. CrossRefPubMedGoogle Scholar
  142. 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. CrossRefPubMedGoogle Scholar
  143. Rodriguez JJ, Verkhratsky A (2011) Neurogenesis in Alzheimer’s disease. J Anat 219:78–89. CrossRefPubMedPubMedCentralGoogle Scholar
  144. 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. CrossRefPubMedGoogle Scholar
  145. 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. CrossRefPubMedGoogle Scholar
  146. 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. CrossRefPubMedGoogle Scholar
  147. 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. CrossRefPubMedGoogle Scholar
  148. Sailor KA, Ming GL, Song H (2006) Neurogenesis as a potential therapeutic strategy for neurodegenerative diseases. Expert Opin Biol Ther 6:879–890. CrossRefPubMedPubMedCentralGoogle Scholar
  149. 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. CrossRefPubMedGoogle Scholar
  150. 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. CrossRefPubMedGoogle Scholar
  151. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  152. Scharfman HE, MacLusky NJ (2008) Estrogen–growth factor interactions and their contributions to neurological disorders. Headache 48:S77–S89. CrossRefPubMedPubMedCentralGoogle Scholar
  153. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  154. 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. CrossRefPubMedGoogle Scholar
  155. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  156. 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. CrossRefPubMedGoogle Scholar
  157. 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. CrossRefPubMedGoogle Scholar
  158. Shohayeb B, Diab M, Ahmed M, Ng DCH (2018) Factors that influence adult neurogenesis as potential therapy. Transl Neurodegener 7:4. CrossRefPubMedPubMedCentralGoogle Scholar
  159. Shughrue PJ, Merchenthaler I (2001) Distribution of estrogen receptor beta immunoreactivity in the rat central nervous system. J Comp Neurol 436:64–81. CrossRefPubMedGoogle Scholar
  160. Simpkins JW, Singh M (2008) More than a decade of estrogen neuroprotection. Alzheimers Dement 4:S131–S136. CrossRefPubMedGoogle Scholar
  161. 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. CrossRefPubMedGoogle Scholar
  162. 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. CrossRefPubMedGoogle Scholar
  163. 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. CrossRefPubMedGoogle Scholar
  164. 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. CrossRefPubMedGoogle Scholar
  165. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  166. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  167. 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. CrossRefPubMedGoogle Scholar
  168. Starkov AA (2008) The role of mitochondria in reactive oxygen species metabolism and signaling. Ann N Y Acad Sci 1147:37–52. CrossRefPubMedPubMedCentralGoogle Scholar
  169. 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. CrossRefPubMedGoogle Scholar
  170. 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. CrossRefPubMedGoogle Scholar
  171. 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. CrossRefPubMedGoogle Scholar
  172. 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. CrossRefPubMedGoogle Scholar
  173. 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. CrossRefPubMedGoogle Scholar
  174. Tensaouti Y, Stephanz EP, Yu TS, Kernie SG (2018) ApoE regulates the development of adult newborn hippocampal neurons. eNeuro 5(4):1–45. CrossRefGoogle Scholar
  175. 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. CrossRefPubMedGoogle Scholar
  176. Toran-Allerand CD (2004) Minireview: a plethora of estrogen receptors in the brain: where will it end? Endocrinology 145:1069–1074. CrossRefPubMedGoogle Scholar
  177. 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. CrossRefPubMedGoogle Scholar
  178. 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. CrossRefPubMedGoogle Scholar
  179. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  180. 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. CrossRefPubMedGoogle Scholar
  181. Vezzani A, Sperk G, Colmers WF (1999) Neuropeptide Y: emerging evidence for a functional role in seizure modulation. Trends Neurosci 22:25–30. CrossRefPubMedGoogle Scholar
  182. 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. CrossRefGoogle Scholar
  183. 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. CrossRefPubMedGoogle Scholar
  184. 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. CrossRefPubMedGoogle Scholar
  185. 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. CrossRefPubMedGoogle Scholar
  186. Wang C, Jie C, Dai X (2014) Possible roles of astrocytes in estrogen neuroprotection during cerebral ischemia. Rev Neurosci 25(2):255–268. CrossRefPubMedGoogle Scholar
  187. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  188. 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 1:131–147PubMedPubMedCentralGoogle Scholar
  189. 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. CrossRefPubMedGoogle Scholar
  190. 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. CrossRefPubMedGoogle Scholar
  191. 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. CrossRefPubMedGoogle Scholar
  192. 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. CrossRefPubMedGoogle Scholar
  193. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  194. 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. CrossRefPubMedGoogle Scholar
  195. 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. CrossRefPubMedGoogle Scholar
  196. 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. CrossRefPubMedGoogle Scholar
  197. 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. CrossRefPubMedGoogle Scholar
  198. 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. CrossRefPubMedGoogle Scholar
  199. 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. CrossRefPubMedGoogle Scholar
  200. 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. CrossRefPubMedGoogle Scholar
  201. 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. CrossRefPubMedGoogle Scholar
  202. 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. CrossRefPubMedGoogle Scholar
  203. 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. CrossRefPubMedGoogle Scholar
  204. 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. CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Sajad Sahab-Negah
    • 1
    • 2
    • 3
  • Vahid Hajali
    • 1
    • 2
  • Hamid Reza Moradi
    • 4
  • Ali Gorji
    • 1
    • 2
    • 3
    • 5
    • 6
    Email author
  1. 1.Neuroscience Research CenterMashhad University of Medical SciencesMashhadIran
  2. 2.Department of Neuroscience, Faculty of MedicineMashhad University of Medical SciencesMashhadIran
  3. 3.Shefa Neuroscience Research CenterKhatam Alanbia HospitalTehranIran
  4. 4.Histology and Embryology Group, Basic Science Department, Faculty of Veterinary MedicineShiraz UniversityShirazIran
  5. 5.Department of Neurosurgery and Department of NeurologyWestfälische Wilhelms-Universität MünsterMünsterGermany
  6. 6.Epilepsy Research CenterWestfälische Wilhelms-Universität MünsterMünsterGermany

Personalised recommendations