Advertisement

Neurotherapeutics

, Volume 16, Issue 3, pp 649–665 | Cite as

The Role of Estrogen in Brain and Cognitive Aging

  • Jason K. Russell
  • Carrie K. Jones
  • Paul A. NewhouseEmail author
Review
  • 139 Downloads

Abstract

There are 3 common physiological estrogens, of which estradiol (E2) is seen to decline rapidly over the menopausal transition. This decline in E2 has been associated with a number of changes in the brain, including cognitive changes, effects on sleep, and effects on mood. These effects have been demonstrated in both rodent and non-human preclinical models. Furthermore, E2 interactions have been indicated in a number of neuropsychiatric disorders, including Alzheimer’s disease, schizophrenia, and depression. In normal brain aging, there are a number of systems that undergo changes and a number of these show interactions with E2, particularly the cholinergic system, the dopaminergic system, and mitochondrial function. E2 treatment has been shown to ameliorate some of the behavioral and morphological changes seen in preclinical models of menopause; however, in clinical populations, the effects of E2 treatment on cognitive changes after menopause are mixed. The future use of sex hormone treatment will likely focus on personalized or precision medicine for the prevention or treatment of cognitive disturbances during aging, with a better understanding of who may benefit from such treatment.

Key Words

Estrogen menopause aging cognition estradiol critical period 

Notes

Acknowledgments

Preparation of this manuscript was partially supported by the National Institute on Aging R01AG047992, Alzheimer’s Association PCTR-16-383171 to PN, and National Institute on Aging 1R01AG054622 to CJ.

Required Author Forms

Disclosure forms provided by the authors are available with the online version of this article.

Supplementary material

13311_2019_766_MOESM1_ESM.pdf (508 kb)
ESM 1 (PDF 508 kb)

References

  1. 1.
    Kuiper GGJM, Carlsson B, Grandien K, et al. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors and α and β. Endocrinology. 1997;138:863–870.Google Scholar
  2. 2.
    Thomas P, Pang Y, Filardo EJ, et al. Identity of an Estrogen Membrane Receptor Coupled to a G Protein in Human Breast Cancer Cells. Endocrinology. 2005;146:624–632.Google Scholar
  3. 3.
    Ryan KJ. Biological aromatization of steroids. J. Biol. Chem. 1959;234:268–272.Google Scholar
  4. 4.
    Ryan KJ. Biochemistry of aromatase: significance to female reproductive physiology. Cancer Res. 1982;42:3342s–3344s.Google Scholar
  5. 5.
    Cooke PS, Nanjappa MK, Ko C, et al. Estrogens in Male Physiology. Physiol. Rev. 2017;97:995–1043.Google Scholar
  6. 6.
    Baker ME. What are the physiological estrogens? Steroids. 2013;337–340.Google Scholar
  7. 7.
    Simerly RB, Swanson LW, Chang C, et al. Distribution of androgen and estrogen receptor mRNA-containing cells in the rat brain: An in situ hybridization study. J. Comp. Neurol. 1990;294:76–95.Google Scholar
  8. 8.
    Jabbour HN, Kelly RW, Fraser HM, et al. Endocrine Regulation of Menstruation. Endocr. Rev. 2006;27:17–46.Google Scholar
  9. 9.
    Brailoiu E, Dun SL, Brailoiu GC, et al. Distribution and characterization of estrogen receptor G protein-coupled receptor 30 in the rat central nervous system. J. Endocrinol. 2007;193:311–321.Google Scholar
  10. 10.
    McKinlay SM, Brambilla DJ, Posner JG. The normal menopause transition. Maturitas. 1992;14:103–115.Google Scholar
  11. 11.
    World Health Organization. Research on the Menopause in the 1990s: Report of a WHO Scientific Group. WHO Tech. Rep. Ser. No. 866. 1996;12–14.Google Scholar
  12. 12.
    Shuster LT, Rhodes DJ, Gostout BS, et al. Premature menopause or early menopause: Long-term health consequences. Maturitas. 2010;65:161–166.Google Scholar
  13. 13.
    Gold EB, Colvin A, Avis N, et al. Longitudinal analysis of the association between vasomotor symptoms and race/ethnicity across the menopausal transition: study of women’s health across the nation. Am. J. Public Health. 2006;96:1226–1235.Google Scholar
  14. 14.
    Freeman EW, Sammel MD, Lin H, et al. Symptoms Associated With Menopausal Transition and Reproductive Hormones in Midlife Women. Obstet. Gynecol. 2007;110:230–240.Google Scholar
  15. 15.
    Kravitz HM, Janssen I, Bromberger JT, et al. Sleep Trajectories Before and After the Final Menstrual Period in The Study of Women’s Health Across the Nation (SWAN). Curr. sleep Med. reports. 2017;3:235–250.Google Scholar
  16. 16.
    Lamar M, Resnick SM, Zonderman AB, et al. Longitudinal changes in verbal memory in older adults: distinguishing the effects of age from repeat testing. Neurology. 2003;60:82–86.Google Scholar
  17. 17.
    Morley JE, Kaiser FE, Perry HM, et al. Longitudinal changes in testosterone, luteinizing hormone, and follicle-stimulating hormone in healthy older men. Metabolism. 1997;46:410–413.Google Scholar
  18. 18.
    Ferrini RL, Barrett-Connor E. Sex Hormones and Age: A Cross-sectional Study of Testosterone and Estradiol and Their Bioavailable Fractions in Community-dwelling Men. Am. J. Epidemiol. 1998;147:750–754.Google Scholar
  19. 19.
    van den Beld AW, de Jong FH, Grobbee DE, et al. Measures of Bioavailable Serum Testosterone and Estradiol and Their Relationships with Muscle Strength, Bone Density, and Body Composition in Elderly Men. J. Clin. Endocrinol. Metab. 2000;85:3276–3282.Google Scholar
  20. 20.
    Finch CE. The menopause and aging, a comparative perspective. J. Steroid Biochem. Mol. Biol. 2014;142:132–141.Google Scholar
  21. 21.
    Long T, Yao JK, Li J, et al. Comparison of transitional vs surgical menopause on monoamine and amino acid levels in the rat brain. Mol. Cell. Endocrinol. 2018;476:139–147.Google Scholar
  22. 22.
    Springer LN, McAsey ME, Flaws JA, et al. Involvement of Apoptosis in 4-Vinylcyclohexene Diepoxide- Induced Ovotoxicity in Rats. Toxicol. Appl. Pharmacol. 1996;139:394–401.Google Scholar
  23. 23.
    Mayer LP, Pearsall NA, Christian PJ, et al. Long-term effects of ovarian follicular depletion in rats by 4-vinylcyclohexene diepoxide. Reprod. Toxicol. 2002;16:775–781.Google Scholar
  24. 24.
    Gilardi K V, Shideler SE, Valverde CR, et al. Characterization of the onset of menopause in the rhesus macaque. Biol. Reprod. 1997;57:335–340.Google Scholar
  25. 25.
    Roberts JA, Gilardi KVK, Lasley B, et al. Reproductive senescence predicts cognitive decline in aged female monkeys. Neuroreport. 1997;8:2047–2051.Google Scholar
  26. 26.
    Hara Y, Park CS, Janssen WGM, et al. Synaptic correlates of memory and menopause in the hippocampal dentate gyrus in rhesus monkeys. Neurobiol. Aging. 2012;33:421.e17–421.e28.Google Scholar
  27. 27.
    Rapp PR, Morrison JH, Roberts JA. Cyclic estrogen replacement improves cognitive function in aged ovariectomized rhesus monkeys. J. Neurosci. 2003;23:5708–5714.Google Scholar
  28. 28.
    Baxter MG, Roberts MT, Gee NA, et al. Multiple clinically-relevant hormone therapy regimens fail to improve cognitive function in aged ovariectomized rhesus monkeys. Neurobiol Aging. 2013;34:1882–1890.Google Scholar
  29. 29.
    Hasegawa Y, Hojo Y, Kojima H, et al. Estradiol rapidly modulates synaptic plasticity of hippocampal neurons: Involvement of kinase networks. Brain Res. 2015;1621:147–161.Google Scholar
  30. 30.
    Pietras RJ, Szego CM. Endometrial cell calcium and oestrogen action. Nature. 1975;253:357–359.Google Scholar
  31. 31.
    Perret S, Dockery P, Harvey B. 17β-Oestradiol stimulates capacitative Ca2+ entry in human endometrial cells. Mol. Cell. Endocrinol. 2001;176:77–84.Google Scholar
  32. 32.
    Lösel R, Wehling M. Nongenomic actions of steroid hormones. Nat. Rev. Mol. Cell Biol. 2003;4:46–55.Google Scholar
  33. 33.
    Liu F, Day M, Muñiz LC, et al. Activation of estrogen receptor-β regulates hippocampal synaptic plasticity and improves memory. Nat. Neurosci. 2008;11:334–343.Google Scholar
  34. 34.
    Spencer-Segal JL, Tsuda MC, Mattei L, et al. Estradiol acts via estrogen receptors alpha and beta on pathways important for synaptic plasticity in the mouse hippocampal formation. Neuroscience. 2012;202:131–146.Google Scholar
  35. 35.
    Boulware MI, Heisler JD, Frick KM. The Memory-Enhancing Effects of Hippocampal Estrogen Receptor Activation Involve Metabotropic Glutamate Receptor Signaling. J. Neurosci. 2013;33:15184–15194.Google Scholar
  36. 36.
    Phan A, Lancaster KE, Armstrong JN, et al. Rapid Effects of Estrogen Receptor α and β Selective Agonists on Learning and Dendritic Spines in Female Mice. Endocrinology. 2011;152:1492–1502.Google Scholar
  37. 37.
    Briz V, Liu Y, Zhu G, et al. A novel form of synaptic plasticity in field CA3 of hippocampus requires GPER1 activation and BDNF release. J. Cell Biol. 2015;210:1225–1237.Google Scholar
  38. 38.
    Revankar CM, Cimino DF, Sklar LA, et al. A Transmembrane Intracellular Estrogen Receptor Mediates Rapid Cell Signaling. Science. 2005;307:1625–1630.Google Scholar
  39. 39.
    Toran-Allerand CD, Guan X, MacLusky NJ, et al. ER-X: a novel, plasma membrane-associated, putative estrogen receptor that is regulated during development and after ischemic brain injury. J. Neurosci. 2002;22:8391–8401.Google Scholar
  40. 40.
    Qiu J, Bosch MA, Tobias SC, et al. Rapid signaling of estrogen in hypothalamic neurons involves a novel G-protein-coupled estrogen receptor that activates protein kinase C. J. Neurosci. 2003;23:9529–9540.Google Scholar
  41. 41.
    Gould E, Woolley CS, Frankfurt M, et al. Gonadal steroids regulate dendritic spine density in hippocampal pyramidal cells in adulthood. J. Neurosci. 1990;10:1286–1291.Google Scholar
  42. 42.
    Hao J, Rapp PR, Leffler AE, et al. Estrogen Alters Spine Number and Morphology in Prefrontal Cortex of Aged Female Rhesus Monkeys. J. Neurosci. 2006;26:2571–2578.Google Scholar
  43. 43.
    Hara Y, Yuk F, Puri R, et al. Estrogen Restores Multisynaptic Boutons in the Dorsolateral Prefrontal Cortex while Promoting Working Memory in Aged Rhesus Monkeys. J. Neurosci. 2016;36:901–910.Google Scholar
  44. 44.
    Albert K, Hiscox J, Boyd B, et al. Estrogen enhances hippocampal gray-matter volume in young and older postmenopausal women: a prospective dose-response study. Neurobiol. Aging. 2017;56:1–6.Google Scholar
  45. 45.
    Goto M, Abe O, Miyati T, et al. 3 Tesla MRI detects accelerated hippocampal volume reduction in postmenopausal women. J. Magn. Reson. Imaging. 2011;33:48–53.Google Scholar
  46. 46.
    Resnick SM, Espeland MA, Jaramillo SA, et al. Postmenopausal hormone therapy and regional brain volumes: the WHIMS-MRI Study. Neurology. 2009;72:135–142.Google Scholar
  47. 47.
    Kim G-W, Park K, Jeong G-W. Effects of Sex Hormones and Age on Brain Volume in Post-Menopausal Women. J. Sex. Med. 2018;15:662–670.Google Scholar
  48. 48.
    Vega JN, Zurkovsky L, Albert K, et al. Altered Brain Connectivity in Early Postmenopausal Women with Subjective Cognitive Impairment. Front. Neurosci. 2016;10:433.Google Scholar
  49. 49.
    Stevens MC, Clark VP, Prestwood KM. Low-dose estradiol alters brain activity. Psychiatry Res. Neuroimaging. 2005;139:199–217.Google Scholar
  50. 50.
    Dumas JA, Kutz AM, Naylor MR, et al. Increased memory load-related frontal activation after estradiol treatment in postmenopausal women. Horm. Behav. 2010;58:929–935.Google Scholar
  51. 51.
    Heikkinen T, Puoliväli J, Tanila H. Effects of long-term ovariectomy and estrogen treatment on maze learning in aged mice. Exp. Gerontol. 2004;39:1277–1283.Google Scholar
  52. 52.
    da Rocha JT, Sampaio TB, Santos Neto JS, et al. Cognitive effects of diphenyl diselenide and estradiol treatments in ovariectomized mice. Neurobiol. Learn. Mem. 2013;99:17–24.Google Scholar
  53. 53.
    Gibbs RB, Chipman AM, Hammond R, et al. Galanthamine plus estradiol treatment enhances cognitive performance in aged ovariectomized rats. Horm. Behav. 2011;60:607–616.Google Scholar
  54. 54.
    Gibbs RB, Mauk R, Nelson D, et al. Donepezil treatment restores the ability of estradiol to enhance cognitive performance in aged rats: evidence for the cholinergic basis of the critical period hypothesis. Horm. Behav. 2009;56:73–83.Google Scholar
  55. 55.
    Jacome LF, Gautreaux C, Inagaki T, et al. Estradiol and ERβ agonists enhance recognition memory, and DPN, an ERβ agonist, alters brain monoamines. Neurobiol. Learn. Mem. 2010;94:488–498.Google Scholar
  56. 56.
    Hammond R, Mauk R, Ninaci D, et al. Chronic treatment with estrogen receptor agonists restores acquisition of a spatial learning task in young ovariectomized rats. Horm. Behav. 2009;56:309–314.Google Scholar
  57. 57.
    Kim J, Szinte JS, Boulware MI, et al. 17β-Estradiol and Agonism of G-protein-Coupled Estrogen Receptor Enhance Hippocampal Memory via Different Cell-Signaling Mechanisms. J. Neurosci. 2016;36:3309–3321.Google Scholar
  58. 58.
    Hawley WR, Grissom EM, Moody NM, et al. Activation of G-protein-coupled receptor 30 is sufficient to enhance spatial recognition memory in ovariectomized rats. Behav. Brain Res. 2014;262:68–73.Google Scholar
  59. 59.
    Gold EB, Sternfeld B, Kelsey JL, et al. Relation of Demographic and Lifestyle Factors to Symptoms in a Multi-Racial/Ethnic Population of Women 40-55 Years of Age. Am. J. Epidemiol. 2000;152:463–473.Google Scholar
  60. 60.
    Woods NF, Mitchell ES, Adams C. Memory functioning among midlife women: Observations from the Seattle Midlife Women’s Health Study. Menopause. 2000. p. 257–265.Google Scholar
  61. 61.
    Drogos LL, Rubin LH, Geller SE, et al. Objective cognitive performance is related to subjective memory complaints in midlife women with moderate to severe vasomotor symptoms. Menopause. 2013;20:1236–1242.Google Scholar
  62. 62.
    Weber MT, Mapstone M, Staskiewicz J, et al. Reconciling subjective memory complaints with objective memory performance in the menopausal transition. Menopause. 2012;19:735–741.Google Scholar
  63. 63.
    Greendale GA, Huang M-H, Wight RG, et al. Effects of the menopause transition and hormone use on cognitive performance in midlife women. Neurology. 2009;72:1850–1857.Google Scholar
  64. 64.
    Freeman EW, Sammel MD, Gross SA, et al. Poor sleep in relation to natural menopause: a population-based 14-year follow-up of midlife women. Menopause. 2015;22:719–726.Google Scholar
  65. 65.
    Cintron D, Lipford M, Larrea-Mantilla L, et al. Efficacy of menopausal hormone therapy on sleep quality: systematic review and meta-analysis. Endocrine. 2017;55:702–711.Google Scholar
  66. 66.
    Freedman RR, Roehrs TA. Effects of REM sleep and ambient temperature on hot flash-induced sleep disturbance. Menopause J. North Am. Menopause Soc. 2006;13:576–583.Google Scholar
  67. 67.
    Freedman RR, Roehrs TA. Sleep disturbance in menopause. Menopause J. North Am. Menopause Soc. 2007;14:826–829.Google Scholar
  68. 68.
    Parmeggiani PL, Zamboni G, Cianci T, et al. Absence of thermoregulatory vasomotor responses during fast wave sleep in cats. Electroencephalogr. Clin. Neurophysiol. 1977;42:372–380.Google Scholar
  69. 69.
    Van Dort CJ, Zachs DP, Kenny JD, et al. Optogenetic activation of cholinergic neurons in the PPT or LDT induces REM sleep. Proc. Natl. Acad. Sci. U. S. A. 2015;112:584–589.Google Scholar
  70. 70.
    Han Y, Shi Y, Xi W, et al. Selective Activation of Cholinergic Basal Forebrain Neurons Induces Immediate Sleep-wake Transitions. Curr. Biol. 2014;24:693–698.Google Scholar
  71. 71.
    Tao MF, Sun DM, Shao HF, et al. Poor sleep in middle-aged women is not associated with menopause per se. Brazilian J. Med. Biol. Res. 2016;49:e4718.Google Scholar
  72. 72.
    Hajali V, Sheibani V, Esmaeili-Mahani S, et al. Female rats are more susceptible to the deleterious effects of paradoxical sleep deprivation on cognitive performance. Behav. Brain Res. 2012;228:311–318.Google Scholar
  73. 73.
    Deurveilher S, Seary ME, Semba K. Ovarian hormones promote recovery from sleep deprivation by increasing sleep intensity in middle-aged ovariectomized rats. Horm. Behav. 2013;63:566–576.Google Scholar
  74. 74.
    Schwartz MD, Mong JA. Estradiol suppresses recovery of REM sleep following sleep deprivation in ovariectomized female rats. Physiol. Behav. 2011;104:962–971.Google Scholar
  75. 75.
    Paul KN, Laposky AD, Turek FW. Reproductive hormone replacement alters sleep in mice. Neurosci. Lett. 2009;463:239–243.Google Scholar
  76. 76.
    Albert K, Newhouse P. Estrogen, stress, and depression: Cognitive and biological interactions. Annu. Rev. Psychol.Google Scholar
  77. 77.
    Kessler RC, Berglund P, Demler O, et al. Lifetime Prevalence and Age-of-Onset Distributions of DSM-IV Disorders in the National Comorbidity Survey Replication. Arch. Gen. Psychiatry. 2005;62:593.Google Scholar
  78. 78.
    Newhouse P, Albert K. Estrogen, Stress, and Depression. JAMA Psychiatry. 2015;72:727.Google Scholar
  79. 79.
    Schmidt PJ, Ben Dor R, Martinez PE, et al. Effects of Estradiol Withdrawal on Mood in Women With Past Perimenopausal Depression. JAMA Psychiatry. 2015;72:714.Google Scholar
  80. 80.
    Jovanovic H, Kocoska-Maras L, Rådestad AF, et al. Effects of estrogen and testosterone treatment on serotonin transporter binding in the brain of surgically postmenopausal women – a PET study. Neuroimage. 2015;106:47–54.Google Scholar
  81. 81.
    Booij L, Does W Van der, Benkelfat C, et al. Predictors of Mood Response to Acute Tryptophan Depletion A Reanalysis. Neuropsychopharmacology. 2002;27:852–861.Google Scholar
  82. 82.
    Halbreich U, Rojansky N, Palter S, et al. Estrogen augments serotonergic activity in postmenopausal women. Biol. Psychiatry. 1995;37:434–441.Google Scholar
  83. 83.
    Moses-Kolko EL, Berga SL, Greer PJ, et al. Widespread increases of cortical serotonin type 2A receptor availability after hormone therapy in euthymic postmenopausal women. Fertil. Steril. 2003;80:554–559.Google Scholar
  84. 84.
    Fink G, Sumner BE, Rosie R, et al. Estrogen control of central neurotransmission: effect on mood, mental state, and memory. Cell. Mol. Neurobiol. 1996;16:325–344.Google Scholar
  85. 85.
    Stokes PE. The potential role of excessive cortisol induced by HPA hyperfunction in the pathogenesis of depression. Eur. Neuropsychopharmacol. 1995;5:77–82.Google Scholar
  86. 86.
    Kirschbaum C, Wust S, Hellhammer D. Consistent sex differences in cortisol responses to psychological stress. Psychosom. Med. 1992;54:648–657.Google Scholar
  87. 87.
    Altemus M. Sex differences in depression and anxiety disorders: potential biological determinants. Horm. Behav. 2006;50:534–538.Google Scholar
  88. 88.
    Kirschbaum C, Kudielka BM, Gaab J, et al. Impact of gender, menstrual cycle phase, and oral contraceptives on the activity of the hypothalamus-pituitary-adrenal axis. Psychosom. Med. 61:154–162.Google Scholar
  89. 89.
    Bartus RT, Dean III RL, Beer B, et al. The Cholinergic Hypothesis of Geriatric Memory Dysfunction. Science (80-. ). 1982;217:408–417.Google Scholar
  90. 90.
    Nordberg A, Winblad B. Reduced number of [3H]nicotine and [3H]acetylcholine binding sites in the frontal cortex of Alzheimer brains. Neurosci. Lett. 1986;72:115–120.Google Scholar
  91. 91.
    Schliebs R, Arendt T. The significance of the cholinergic system in the brain during aging and in Alzheimer’s disease. J. Neural Transm. 2006;113:1625–1644.Google Scholar
  92. 92.
    Colombo PJ, Gallagher M. Individual Differences in Spatial Memory and Striatal ChAT Activity among Young and Aged Rats. Neurobiol. Learn. Mem. 1998;70:314–327.Google Scholar
  93. 93.
    Rogers SL, Farlow MR, Doody RS, et al. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer’s disease. Donepezil Study Group. Neurology. 1998;50:136–145.Google Scholar
  94. 94.
    Raskind MA, Peskind ER, Wessel T, et al. Galantamine in AD: A 6-month randomized, placebo-controlled trial with a 6-month extension. The Galantamine USA-1 Study Group. Neurology. 2000;54:2261–2268.Google Scholar
  95. 95.
    Rösler M, Anand R, Cicin-Sain A, et al. Efficacy and safety of rivastigmine in patients with Alzheimer’s disease: international randomised controlled trial. BMJ. 1999;318:633–638.Google Scholar
  96. 96.
    Hammond R, Gibbs RB. GPR30 is positioned to mediate estrogen effects on basal forebrain cholinergic neurons and cognitive performance. Brain Res. 2011;1379:53–60.Google Scholar
  97. 97.
    Shughrue PJ, Scrimo PJ, Merchenthaler I. Estrogen binding and estrogen receptor characterization (ERalpha and ERbeta) in the cholinergic neurons of the rat basal forebrain. Neuroscience. 2000;96:41–49.Google Scholar
  98. 98.
    Dohanich GP, Fader AJ, Javorsky DJ. Estrogen and estrogen-progesterone treatments counteract the effect of scopolamine on reinforced T-maze alternation in female rats. Behav. Neurosci. 1994;108:988–992.Google Scholar
  99. 99.
    Tanabe F, Miyasaka N, Kubota T, et al. Estrogen and progesterone improve scopolamine-induced impairment of spatial memory. J. Med. Dent. Sci. 2004;51:89–98.Google Scholar
  100. 100.
    Fader AJ, Johnson PE., Dohanich GP. Estrogen Improves Working But Not Reference Memory and Prevents Amnestic Effects of Scopolamine on a Radial-Arm Maze. Pharmacol. Biochem. Behav. 1999;62:711–717.Google Scholar
  101. 101.
    Gibbs RB, Burke AM, Johnson DA. Estrogen Replacement Attenuates Effects of Scopolamine and Lorazepam on Memory Acquisition and Retention. Horm. Behav. 1998;34:112–125.Google Scholar
  102. 102.
    Knüsel B, Beck KD, Winslow JW, et al. Brain-derived neurotrophic factor administration protects basal forebrain cholinergic but not nigral dopaminergic neurons from degenerative changes after axotomy in the adult rat brain. J. Neurosci. 1992;12:4391–4402.Google Scholar
  103. 103.
    Morse JK, Wiegand SJ, Anderson K, et al. Brain-derived neurotrophic factor (BDNF) prevents the degeneration of medial septal cholinergic neurons following fimbria transection. J. Neurosci. 1993;13:4146–4156.Google Scholar
  104. 104.
    Alderson RF, Alterman AL, Barde Y-A, et al. Brain-derived neurotrophic factor increases survival and differentiated functions of rat septal cholinergic neurons in culture. Neuron. 1990;5:297–306.Google Scholar
  105. 105.
    Hefti F. Nerve growth factor promotes survival of septal cholinergic neurons after fimbrial transections. J. Neurosci. 1986;6:2155–2162.Google Scholar
  106. 106.
    Fischer W, Wictorin K, Björklund A, et al. Amelioration of cholinergic neuron atrophy and spatial memory impairment in aged rats by nerve growth factor. Nature. 1987;329:65–68.Google Scholar
  107. 107.
    Gibbs RB. Estrogen and Nerve Growth Factor-related Systems in Brain. Ann. N. Y. Acad. Sci. 1994;743:165–196.Google Scholar
  108. 108.
    Singh M, Sétáló G, Guan X, et al. Estrogen-induced activation of mitogen-activated protein kinase in cerebral cortical explants: convergence of estrogen and neurotrophin signaling pathways. J. Neurosci. 1999;19:1179–1188.Google Scholar
  109. 109.
    Toran-Allerand CD, Miranda RC, Bentham WD, et al. Estrogen receptors colocalize with low-affinity nerve growth factor receptors in cholinergic neurons of the basal forebrain. Proc. Natl. Acad. Sci. U. S. A. 1992;89:4668–4672.Google Scholar
  110. 110.
    Gibbs RB, Wu D, Hersh LB, et al. Effects of Estrogen Replacement on the Relative Levels of Choline Acetyltransferase, trkA, and Nerve Growth Factor Messenger RNAs in the Basal Forebrain and Hippocampal Formation of Adult Rats. Exp. Neurol. 1994;129:70–80.Google Scholar
  111. 111.
    McMillan PJ, Singer CA, Dorsa DM. The effects of ovariectomy and estrogen replacement on trkA and choline acetyltransferase mRNA expression in the basal forebrain of the adult female Sprague-Dawley rat. J. Neurosci. 1996;16:1860–1865.Google Scholar
  112. 112.
    Gibbs RB. 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. 1998;787:259–268.Google Scholar
  113. 113.
    Singer CA, McMillan PJ, Dobie DJ, et al. Effects of estrogen replacement on choline acetyltransferase and trkA mRNA expression in the basal forebrain of aged rats. Brain Res. 1998;789:343–346.Google Scholar
  114. 114.
    Smith YR, Minoshima S, Kuhl DE, et al. Effects of Long-Term Hormone Therapy on Cholinergic Synaptic Concentrations in Healthy Postmenopausal Women. J. Clin. Endocrinol. Metab. 2001;86:679–684.Google Scholar
  115. 115.
    Smith YR, Bowen L, Love TM, et al. Early Initiation of Hormone Therapy in Menopausal Women Is Associated with Increased Hippocampal and Posterior Cingulate Cholinergic Activity. J. Clin. Endocrinol. Metab. 2011;96:E1761–E1770.Google Scholar
  116. 116.
    Dumas JA, Kutz AM, Naylor MR, et al. Estradiol treatment altered anticholinergic-related brain activation during working memory in postmenopausal women. Neuroimage. 2012;60:1394–1403.Google Scholar
  117. 117.
    Newhouse P, Albert K, Astur R, et al. Tamoxifen Improves Cholinergically Modulated Cognitive Performance in Postmenopausal Women. Neuropsychopharmacology. 2013;38:2632–2643.Google Scholar
  118. 118.
    Bäckman L, Ginovart N, Dixon RA, et al. Age-Related Cognitive Deficits Mediated by Changes in the Striatal Dopamine System. Am. J. Psychiatry. 2000;157:635–637.Google Scholar
  119. 119.
    Erixon-Lindroth N, Farde L, Robins Wahlin T-B, et al. The role of the striatal dopamine transporter in cognitive aging. Psychiatry Res. Neuroimaging. 2005;138:1–12.Google Scholar
  120. 120.
    Rinne JO, Lönnberg P, Marjamäki P. Age-dependent decline in human brain dopamine D1 and D2 receptors. Brain Res. 1990;508:349–352.Google Scholar
  121. 121.
    Wang Y, Chan GLY, Holden JE, et al. Age-dependent decline of dopamine D1 receptors in human brain: A PET study. Synapse. 1998;30:56–61.Google Scholar
  122. 122.
    Kish SJ, Shannak K, Rajput A, et al. Aging Produces a Specific Pattern of Striatal Dopamine Loss: Implications for the Etiology of Idiopathic Parkinson’s Disease. J. Neurochem. 1992;58:642–648.Google Scholar
  123. 123.
    Seeman P, Bzowej NH, Guan H-C, et al. Human brain dopamine receptors in children and aging adults. Synapse. 1987;1:399–404.Google Scholar
  124. 124.
    Simon H, Taghzouti K, Le Moal M. Deficits in spatial-memory tasks following lesions of septal dopaminergic terminals in the rat. Behav. Brain Res. 1986;19:7–16.Google Scholar
  125. 125.
    Baunez C, Robbins TW. Effects of dopamine depletion of the dorsal striatum and further interaction with subthalamic nucleus lesions in an attentional task in the rat. Neuroscience. 1999;92:1343–1356.Google Scholar
  126. 126.
    Brown RG, Marsden CD. ‘Subcorttcal dementia’: The neuropsychological evidence. Neuroscience. 1988;25:363–387.Google Scholar
  127. 127.
    Lawrence A, Weeks RA, Brooks DJ, et al. The relationship between striatal dopamine receptor binding and cognitive performance in Huntington’s disease. Brain. 1998;121:1343–1355.Google Scholar
  128. 128.
    Luciana M, Collins PF. Dopaminergic Modulation of Working Memory for Spatial but Not Object Cues in Normal Humans. J. Cogn. Neurosci. 1997;9:330–347.Google Scholar
  129. 129.
    Callier S, Le Saux M, Lhiaubet A-M, et al. Evaluation of the protective effect of oestradiol against toxicity induced by 6-hydroxydopamine and 1-methyl-4-phenylpyridinium ion (MPP+) towards dopaminergic mesencephalic neurones in primary culture. J. Neurochem. 2002;80:307–316.Google Scholar
  130. 130.
    Morissette M, Paolo T Di. Effect of Chronic Estradiol and Progesterone Treatments of Ovariectomized Rats on Brain Dopamine Uptake Sites. J. Neurochem. 1993;60:1876–1883.Google Scholar
  131. 131.
    Leranth C, Roth RH, Elsworth JD, et al. Estrogen is essential for maintaining nigrostriatal dopamine neurons in primates: implications for Parkinson’s disease and memory. J. Neurosci. 2000;20:8604–8609.Google Scholar
  132. 132.
    Dumas JA, Filippi CG, Newhouse PA, et al. Dopaminergic contributions to working memory-related brain activation in postmenopausal women. Menopause. 2017;24:163–170.Google Scholar
  133. 133.
    Kambeitz J, Abi-Dargham A, Kapur S, et al. Alterations in cortical and extrastriatal subcortical dopamine function in schizophrenia: systematic review and meta-analysis of imaging studies. Br. J. Psychiatry. 2014;204:420–429.Google Scholar
  134. 134.
    Howes OD, McCutcheon R, Owen MJ, et al. The Role of Genes, Stress, and Dopamine in the Development of Schizophrenia. Biol. Psychiatry. 2017;81:9–20.Google Scholar
  135. 135.
    Howes OD, Montgomery AJ, Asselin M-C, et al. Elevated Striatal Dopamine Function Linked to Prodromal Signs of Schizophrenia. Arch. Gen. Psychiatry. 2009;66:13.Google Scholar
  136. 136.
    Häfner H, Riecher-Rössler A, An Der Heiden W, et al. Generating and testing a causal explanation of the gender difference in age at first onset of schizophrenia. Psychol. Med. 1993;23:925–940.Google Scholar
  137. 137.
    Cohen RZ, Seeman M V, Gotowiec A, et al. Earlier puberty as a predictor of later onset of schizophrenia in women. Am. J. Psychiatry. 1999;156:1059–1064.Google Scholar
  138. 138.
    Grigoriadis S, Seeman M V. The Role of Estrogen in Schizophrenia: Implications for Schizophrenia Practice Guidelines for Women. Can. J. Psychiatry. 2002;47:437–442.Google Scholar
  139. 139.
    Akhondzadeh S, Nejatisafa AA, Amini H, et al. Adjunctive estrogen treatment in women with chronic schizophrenia: a double-blind, randomized, and placebo-controlled trial. Prog. Neuro-Psychopharmacology Biol. Psychiatry. 2003;27:1007–1012.Google Scholar
  140. 140.
    Kindler J, Weickert CS, Skilleter AJ, et al. Selective Estrogen Receptor Modulation Increases Hippocampal Activity during Probabilistic Association Learning in Schizophrenia. Neuropsychopharmacology. 2015;40:2388–2397.Google Scholar
  141. 141.
    Weickert TW, Weinberg D, Lenroot R, et al. Adjunctive raloxifene treatment improves attention and memory in men and women with schizophrenia. Mol. Psychiatry. 2015;20:685–694.Google Scholar
  142. 142.
    Van Den Eeden SK, Tanner CM, Bernstein AL, et al. Incidence of Parkinson’s disease: variation by age, gender, and race/ethnicity. Am. J. Epidemiol. 2003;157:1015–1022.Google Scholar
  143. 143.
    Benedetti MD, Maraganore DM, Bower JH, et al. Hysterectomy, menopause, and estrogen use preceding Parkinson’s disease: An exploratory case-control study. Mov. Disord. 2001;16:830–837.Google Scholar
  144. 144.
    Lv M, Zhang Y, Chen G, et al. Reproductive factors and risk of Parkinson’s disease in women: A meta-analysis of observational studies. Behav. Brain Res. 2017;335:103–110.Google Scholar
  145. 145.
    Liu R, Baird D, Park Y, et al. Female reproductive factors, menopausal hormone use, and Parkinson’s disease. Mov. Disord. 2014;29:889–896.Google Scholar
  146. 146.
    Litim N, Morissette M, Di Paolo T. Neuroactive gonadal drugs for neuroprotection in male and female models of Parkinson’s disease. Neurosci. Biobehav. Rev. 2016;67:79–88.Google Scholar
  147. 147.
    Marder K, Tang MX, Alfaro B, et al. Postmenopausal estrogen use and Parkinson’s disease with and without dementia. Neurology. 1998;50:1141–1143.Google Scholar
  148. 148.
    Labandeira-Garcia JL, Rodriguez-Perez AI, Valenzuela R, et al. Menopause and Parkinson’s disease. Interaction between estrogens and brain renin-angiotensin system in dopaminergic degeneration. Front. Neuroendocrinol. 2016;43:44–59.Google Scholar
  149. 149.
    Re RN. Tissue renin angiotensin systems. Med. Clin. North Am. 2004;88:19–38.Google Scholar
  150. 150.
    Garrido AM, Griendling KK. NADPH oxidases and angiotensin II receptor signaling. Mol. Cell. Endocrinol. 2009;302:148–158.Google Scholar
  151. 151.
    Garrido-Gil P, Valenzuela R, Villar-Cheda B, et al. Expression of angiotensinogen and receptors for angiotensin and prorenin in the monkey and human substantia nigra: an intracellular renin-angiotensin system in the nigra. Brain Struct. Funct. 2013;218:373–388.Google Scholar
  152. 152.
    Muñoz A, Rey P, Guerra MJ, et al. Reduction of dopaminergic degeneration and oxidative stress by inhibition of angiotensin converting enzyme in a MPTP model of parkinsonism. Neuropharmacology. 2006;51:112–120.Google Scholar
  153. 153.
    Joglar B, Rodriguez-Pallares J, Rodriguez-Perez AI, et al. The inflammatory response in the MPTP model of Parkinson’s disease is mediated by brain angiotensin: relevance to progression of the disease. J. Neurochem. 2009;109:656–669.Google Scholar
  154. 154.
    Rodriguez-Perez AI, Borrajo A, Valenzuela R, et al. Critical period for dopaminergic neuroprotection by hormonal replacement in menopausal rats. Neurobiol. Aging. 2015;36:1194–1208.Google Scholar
  155. 155.
    Harman D. Free radical theory of aging: Consequences of mitochondrial aging. Age (Omaha). 1983;6:86–94.Google Scholar
  156. 156.
    Swerdlow RH, Khan SM. A “mitochondrial cascade hypothesis” for sporadic Alzheimer’s disease. Med. Hypotheses. 2004;63:8–20.Google Scholar
  157. 157.
    Croteau E, Castellano CA, Fortier M, et al. A cross-sectional comparison of brain glucose and ketone metabolism in cognitively healthy older adults, mild cognitive impairment and early Alzheimer’s disease. Exp. Gerontol. 2018;107:18–26.Google Scholar
  158. 158.
    Mosconi L, Mistur R, Switalski R, et al. FDG-PET changes in brain glucose metabolism from normal cognition to pathologically verified Alzheimer’s disease. Eur. J. Nucl. Med. Mol. Imaging. 2009;36:811–822.Google Scholar
  159. 159.
    Yao J, Irwin RW, Zhao L, et al. Mitochondrial bioenergetic deficit precedes Alzheimer’s pathology in female mouse model of Alzheimer’s disease. Proc. Natl. Acad. Sci. U. S. A. 2009;106:14670–14675.Google Scholar
  160. 160.
    Mosconi L, Berti V, Quinn C, et al. Perimenopause and emergence of an Alzheimer’s bioenergetic phenotype in brain and periphery. PLoS One. 2017;12:e0185926.Google Scholar
  161. 161.
    Yin F, Yao J, Sancheti H, et al. The perimenopausal aging transition in the female rat brain: decline in bioenergetic systems and synaptic plasticity. Neurobiol. Aging. 2015;36:2282–2295.Google Scholar
  162. 162.
    Rasgon NL, Silverman D, Siddarth P, et al. Estrogen use and brain metabolic change in postmenopausal women. Neurobiol. Aging. 2005;26:229–235.Google Scholar
  163. 163.
    Schmidt R, Schmidt H, Curb JD, et al. Early inflammation and dementia: A 25-year follow-up of the Honolulu-Asia aging study. Ann. Neurol. 2002;52:168–174.Google Scholar
  164. 164.
    Teunissen CE, van Boxtel MPJ, Bosma H, et al. Inflammation markers in relation to cognition in a healthy aging population. J. Neuroimmunol. 2003;134:142–150.Google Scholar
  165. 165.
    Banks WA, Farr SA, La Scola ME, et al. Intravenous human interleukin-1alpha impairs memory processing in mice: dependence on blood-brain barrier transport into posterior division of the septum. J. Pharmacol. Exp. Ther. 2001;299:536–541.Google Scholar
  166. 166.
    Jiang Q, Li W, Sun J, et al. Inhibitory effect of estrogen receptor beta on P2X3 receptors during inflammation in rats. Purinergic Signal. 2017;13:105–117.Google Scholar
  167. 167.
    Cipolla MJ, Godfrey JA, Wiegman MJ. The effect of ovariectomy and estrogen on penetrating brain arterioles and blood-brain barrier permeability. Microcirculation. 2009;16:685–693.Google Scholar
  168. 168.
    Brown CM, Mulcahey TA, Filipek NC, et al. Production of proinflammatory cytokines and chemokines during neuroinflammation: novel roles for estrogen receptors alpha and beta. Endocrinology. 2010;151:4916–4925.Google Scholar
  169. 169.
    Pfeilschifter J, Köditz R, Pfohl M, et al. Changes in Proinflammatory Cytokine Activity after Menopause. Endocr. Rev. 2002;23:90–119.Google Scholar
  170. 170.
    Störk S, von Schacky C, Angerer P. The effect of 17beta-estradiol on endothelial and inflammatory markers in postmenopausal women: a randomized, controlled trial. Atherosclerosis. 2002;165:301–307.Google Scholar
  171. 171.
    Kalyan S, Hitchcock CL, Pudek M, et al. Acute Effects of Premenopausal Hysterectomy with Bilateral Oophorectomy on Serum Lipids, Hormonal Values, Inflammatory Markers, and Metabolism. J. Gynecol. Surg. 2011;27:9–15.Google Scholar
  172. 172.
    Calsolaro V, Edison P. Neuroinflammation in Alzheimer’s disease: Current evidence and future directions. Alzheimer’s Dement. 2016;12:719–732.Google Scholar
  173. 173.
    Glass CK, Saijo K, Winner B, et al. Mechanisms underlying inflammation in neurodegeneration. Cell. 2010;140:918–934.Google Scholar
  174. 174.
    Shumaker SA, Legault C, Kuller L, et al. Conjugated Equine Estrogens and Incidence of Probable Dementia and Mild Cognitive Impairment in Postmenopausal Women: Women’s Health Initiative Memory Study. JAMA. 2004;291:2947.Google Scholar
  175. 175.
    Espeland MA, Rapp SR, Shumaker SA, et al. Conjugated Equine Estrogens and Global Cognitive Function in Postmenopausal Women: Women’s Health Initiative Memory Study. JAMA. 2004;291:2959.Google Scholar
  176. 176.
    Sherwin BB. Estrogen therapy: is time of initiation critical for neuroprotection? Nat. Rev. Endocrinol. 2009;5:620–627.Google Scholar
  177. 177.
    Maki PM, Zonderman AB, Resnick SM. Enhanced Verbal Memory in Nondemented Elderly Women Receiving Hormone-Replacement Therapy. Am. J. Psychiatry. 2001;158:227–233.Google Scholar
  178. 178.
    Resnick SM, Metter EJ, Zonderman AB. Estrogen replacement therapy and longitudinal decline in visual memory. A possible protective effect? Neurology. 1997;49:1491–1497.Google Scholar
  179. 179.
    Hao J, Rapp PR, Janssen WGM, et al. Interactive effects of age and estrogen on cognition and pyramidal neurons in monkey prefrontal cortex. Proc. Natl. Acad. Sci. U. S. A. 2007;104:11465–11470.Google Scholar
  180. 180.
    Kohama SG, Renner L, Landauer N, et al. Effect of Ovarian Hormone Therapy on Cognition in the Aged Female Rhesus Macaque. J. Neurosci. 2016;36:10416–10424.Google Scholar
  181. 181.
    Gibbs RB. Long-term treatment with estrogen and progesterone enhances acquisition of a spatial memory task by ovariectomized aged rats☆. Neurobiol. Aging. 2000;21:107–116.Google Scholar
  182. 182.
    Gibbs RB. Estrogen Therapy and Cognition: A Review of the Cholinergic Hypothesis. Endocr. Rev. 2010;31:224–253.Google Scholar
  183. 183.
    Gonzalez GA, Hofer MP, Syed YA, et al. Tamoxifen accelerates the repair of demyelinated lesions in the central nervous system. Sci. Rep. 2016;6:31599.Google Scholar
  184. 184.
    Baez-Jurado E, Rincón-Benavides MA, Hidalgo-Lanussa O, et al. Molecular mechanisms involved in the protective actions of Selective Estrogen Receptor Modulators in brain cells. Front. Neuroendocrinol. 2019;52:44–64.Google Scholar
  185. 185.
    Ishihara Y, Itoh K, Ishida A, et al. Selective estrogen-receptor modulators suppress microglial activation and neuronal cell death via an estrogen receptor-dependent pathway. J. Steroid Biochem. Mol. Biol. 2015;145:85–93.Google Scholar
  186. 186.
    Aisen PS, Cummings J, Jack CR, et al. On the path to 2025: understanding the Alzheimer’s disease continuum. Alzheimers. Res. Ther. 2017;9:60.Google Scholar
  187. 187.
    Farrer LA, Cupples LA, Haines JL, et al. Effects of Age, Sex, and Ethnicity on the Association Between Apolipoprotein E Genotype and Alzheimer Disease. JAMA. 1997;278:1349.Google Scholar
  188. 188.
    Bove R, Secor E, Chibnik LB, et al. Age at surgical menopause influences cognitive decline and Alzheimer pathology in older women. Neurology. 2014;82:222–229.Google Scholar
  189. 189.
    Zandi PP, Carlson MC, Plassman BL, et al. Hormone Replacement Therapy and Incidence of Alzheimer Disease in Older Women. The Cache County Study. JAMA. 2002;288:2123.Google Scholar
  190. 190.
    Paganini-Hill A, Henderson VW. Estrogen Replacement Therapy and Risk of Alzheimer Disease. Arch. Intern. Med. 1996;156:2213.Google Scholar
  191. 191.
    Kantarci K, Lowe VJ, Lesnick TG, et al. Early Postmenopausal Transdermal 17β-Estradiol Therapy and Amyloid-β Deposition. J. Alzheimers. Dis. 2016;53:547–556.Google Scholar
  192. 192.
    Merlo S, Spampinato SF, Sortino MA. Estrogen and Alzheimer’s disease: Still an attractive topic despite disappointment from early clinical results. Eur. J. Pharmacol. 2017;817:51–58.Google Scholar
  193. 193.
    Jaffe AB, Toran-Allerand CD, Greengard P, et al. Estrogen regulates metabolism of Alzheimer amyloid β precursor protein. J. Biol. Chem. 1994;269:13065–13068.Google Scholar
  194. 194.
    Manthey D, Heck S, Engert S, et al. Estrogen induces a rapid secretion of amyloid β precursor protein via the mitogen-activated protein kinase pathway. Eur. J. Biochem. 2001;268:4285–4291.Google Scholar
  195. 195.
    Goodenough S, Schäfer M, Behl C. Estrogen-induced cell signalling in a cellular model of Alzheimer’s disease. J. Steroid Biochem. Mol. Biol. 2003;84:301–305.Google Scholar
  196. 196.
    Merlo S, Sortino MA. Estrogen activates matrix metalloproteinases-2 and -9 to increase beta amyloid degradation. Mol. Cell. Neurosci. 2012;49:423–429.Google Scholar
  197. 197.
    Xiao Z-M, Sun L, Liu Y-M, et al. Estrogen Regulation of the Neprilysin Gene Through A Hormone-Responsive Element. J. Mol. Neurosci. 2009;39:22–26.Google Scholar
  198. 198.
    Liang K, Yang L, Yin C, et al. Estrogen stimulates degradation of beta-amyloid peptide by up-regulating neprilysin. J. Biol. Chem. 2010;285:935–942.Google Scholar
  199. 199.
    Alvarez De La Rosa M, Silva I, Nilsen J, et al. Estradiol Prevents Neural Tau Hyperphosphorylation Characteristic of Alzheimer’s Disease. Ann. N. Y. Acad. Sci. 2005;1052:210–224.Google Scholar
  200. 200.
    Zhang Z, Simpkins JW. Okadaic acid induces tau phosphorylation in SH-SY5Y cells in an estrogen-preventable manner. Brain Res. 2010;1345:176–181.Google Scholar
  201. 201.
    Wibowo E, Calich HJ, Currie RW, et al. Prolonged androgen deprivation may influence the autoregulation of estrogen receptors in the brain and pelvic floor muscles of male rats. Behav. Brain Res. 2015;286:128–135.Google Scholar
  202. 202.
    Matousek RH, Sherwin BB. A randomized controlled trial of add-back estrogen or placebo on cognition in men with prostate cancer receiving an antiandrogen and a gonadotropin-releasing hormone analog. Psychoneuroendocrinology. 2010;35:215–225.Google Scholar
  203. 203.
    Taxel P, Stevens MC, Trahiotis M, et al. The Effect of Short-Term Estradiol Therapy on Cognitive Function in Older Men Receiving Hormonal Suppression Therapy for Prostate Cancer. J. Am. Geriatr. Soc. 2004;52:269–273.Google Scholar
  204. 204.
    Wu LM, Diefenbach MA, Gordon WA, et al. Cognitive problems in patients on androgen deprivation therapy: A qualitative pilot study. Urol Oncol. 2013;31.Google Scholar
  205. 205.
    Hogervorst E, De Jager C, Budge M, et al. Serum levels of estradiol and testosterone and performance in different cognitive domains in healthy elderly men and women. Psychoneuroendocrinology. 2004;29:405–421.Google Scholar
  206. 206.
    Carlson LE, Sherwin BB. Higher levels of plasma estradiol and testosterone in healthy elderly men compared with age-matched women may protect aspects of explicit memory. Menopause. 7:168–177.Google Scholar
  207. 207.
    Barrett-Connor E, Goodman-Gruen D, Patay B. Endogenous Sex Hormones and Cognitive Function in Older Men. J. Clin. Endocrinol. Metab. 1999;84:3681–3685.Google Scholar
  208. 208.
    Shumaker SA, Legault C, Rapp SR, et al. Estrogen Plus Progestin and the Incidence of Dementia and Mild Cognitive Impairment in Postmenopausal Women. JAMA. 2003;289:2651.Google Scholar
  209. 209.
    Maki PM, Henderson VW. Hormone therapy, dementia, and cognition: the Women’s Health Initiative 10 years on. Climacteric. 2012;15:256–262.Google Scholar
  210. 210.
    Depypere H, Vierin A, Weyers S, et al. Alzheimer’s disease, apolipoprotein E and hormone replacement therapy. Maturitas. 2016;94:98–105.Google Scholar
  211. 211.
    Schneider LS, Farlow MR, Henderson VW, et al. Effects of estrogen replacement therapy on response to tacrine in patients with Alzheimer’s disease. Neurology. 1996;46:1580–1584.Google Scholar
  212. 212.
    Ghoshal A, Rook JM, Dickerson JW, et al. Potentiation of M1 Muscarinic Receptor Reverses Plasticity Deficits and Negative and Cognitive Symptoms in a Schizophrenia Mouse Model. Neuropsychopharmacology. 2016;41:598–610.Google Scholar
  213. 213.
    Foster DJ, Choi DL, Jeffrey Conn P, et al. Activation of M1 and M4 muscarinic receptors as potential treatments for Alzheimer’s disease and schizophrenia. Neuropsychiatr. Dis. Treat. 2014;10:183–191.Google Scholar
  214. 214.
    Rook JM, Bertron JL, Cho HP, et al. A novel M1 PAM VU0486846 exerts efficacy in cognition models without displaying agonist activity or cholinergic toxicity. ACS Chem. Neurosci. 2018;19:2274–2285.Google Scholar
  215. 215.
    Uslaner JM, Kuduk SD, Wittmann M, et al. Preclinical to Human Translational Pharmacology of the Novel M1 Positive Allosteric Modulator MK-7622. J. Pharmacol. Exp. Ther. 2018;365:556–566.Google Scholar
  216. 216.
    Bubser M, Byun N, Wood MR, et al. Muscarinic receptor pharmacology and circuitry for the modulation of cognition. Handb. Exp. Pharmacol. 2012.Google Scholar
  217. 217.
    Gould RW, Dencker D, Grannan M, et al. Role for the M1 Muscarinic Acetylcholine Receptor in Top-Down Cognitive Processing Using a Touchscreen Visual Discrimination Task in Mice. ACS Chem. Neurosci. 2015;6:1683–1695.Google Scholar
  218. 218.
    Grannan MD, Mielnik CA, Moran SP, et al. Prefrontal Cortex-Mediated Impairments in a Genetic Model of NMDA Receptor Hypofunction Are Reversed by the Novel M1 PAM VU6004256. ACS Chem. Neurosci. 2017;7:1706–1716.Google Scholar
  219. 219.
    Jones CK, Byun N, Bubser M. Muscarinic and Nicotinic Acetylcholine Receptor Agonists and Allosteric Modulators for the Treatment of Schizophrenia. Neuropsychopharmacology. 2012;37:16–42.Google Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2019

Authors and Affiliations

  • Jason K. Russell
    • 1
    • 2
  • Carrie K. Jones
    • 1
    • 2
  • Paul A. Newhouse
    • 3
    • 4
    Email author
  1. 1.Department of PharmacologyVanderbilt UniversityNashvilleUSA
  2. 2.Vanderbilt Center for Neuroscience Drug DiscoveryVanderbilt UniversityNashvilleUSA
  3. 3.Center for Cognitive Medicine, Department of Psychiatry and Behavioral SciencesVanderbilt University Medical CenterNashvilleUSA
  4. 4.Geriatric Research, Education, and Clinical Center (GRECC)Tennessee VA Health SystemsNashvilleUSA

Personalised recommendations