Abstract
Ovarian estrogens (mainly 17β estradiol, E2) have been involved in the regulation of the structure of hippocampus, the center of spatial memory. In recent years, high levels of aromatase (AROM), the estrogen synthase, has been localized in hippocampus; and this hippocampus-derived E2 seems to be functional in synaptic plasticity and spatial memory as ovarian E2 does. However, the contribution of ovarian E2 and hippocampal E2 to spatial memory and neural plasticity remains unclear. In this study, AROM-specific RNA interference AAVs (shAROM) were constructed and injected into the hippocampus of control or ovariectomized (OVX) mice. Four weeks later the spatial learning and memory behavior was examined with Morris water maze, the expression of hippocampal Aβ related proteins, selected synaptic proteins and CA1 synapse density, actin polymerization related proteins and CA1 spine density were also examined. The results showed that while OVX and hippocampal shAROM contributed similarly to most of the parameters examined, shAROM induced more increase in BACE1 (amyloidogenic β-secretase), more decrease in neprilysin (Aβ remover) and Profilin-1 (actin polymerization inducer). More importantly, combined OVX and shAROM treatment displayed most significant impairment of spatial learning and memory as well as decrease in synaptic plasticity compared to OVX or shAROM alone. In conclusion, the above results clearly demonstrated the crucial role of hippocampal E2 in the regulation of the structure and function of hippocampus besides ovarian E2, indicating that hippocampal E2 content should also be taken into consideration during estrogenic replacement.
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References
Henderson VW (2014) Alzheimer’s disease: review of hormone therapy trials and implications for treatment and prevention after menopause. J Steroid Biochem Mol Biol 142:99–106
Jaroudi W, Garami J, Garrido S, Hornberger M, Keri S, Moustafa AA (2017) Factors underlying cognitive decline in old age and Alzheimer’s disease: the role of the hippocampus. Rev Neurosci 28:705–714
Woolley CS, Gould E, Frankfurt M, McEwen BS (1990) Naturally occurring fluctuation in dendritic spine density on adult hippocampal pyramidal neurons. J Neurosci 10:4035–4039
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
Liu M, Xing F, Bian C, Zhao Y, Zhao J, Liu Y, Zhang J (2019) Letrozole induces worse hippocampal synaptic and dendritic changes and spatial memory impairment than ovariectomy in adult female mice. Neurosci Lett 706:61–67
Xiao Q, Luo Y, Lv F, He Q, Wu H, Chao F, Qiu X, Zhang L, Gao Y, Huang C, Wang S, Zhou C, Zhang Y, Jiang L, Tang Y (2018) Protective effects of 17beta-estradiol on hippocampal myelinated fibers in ovariectomized middle-aged rats. Neuroscience 385:143–153
Lord C, Buss C, Lupien SJ, Pruessner JC (2008) Hippocampal volumes are larger in postmenopausal women using estrogen therapy compared to past users, never users and men: a possible window of opportunity effect. Neurobiol Aging 29:95–101
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 227:100–108
Iivonen S, Heikkinen T, Puolivali J, Helisalmi S, Hiltunen M, Soininen H, Tanila H (2006) Effects of estradiol on spatial learning, hippocampal cytochrome P450 19, and estrogen alpha and beta mRNA levels in ovariectomized female mice. Neuroscience 137:1143–1152
Frick KM, Fernandez SM, Bulinski SC (2002) Estrogen replacement improves spatial reference memory and increases hippocampal synaptophysin in aged female mice. Neuroscience 115:547–558
Zhang YY, Liu MY, Liu Z, Zhao JK, Zhao YG, He L, Li W, Zhang JQ (2019) GPR30-mediated estrogenic regulation of actin polymerization and spatial memory involves SRC-1 and PI3K-mTORC2 in the hippocampus of female mice. CNS Neurosci Ther 25:714–733
Zhao Y, He L, Zhang Y, Zhao J, Liu Z, Xing F, Liu M, Feng Z, Li W, Zhang J (2017) Estrogen receptor alpha and beta regulate actin polymerization and spatial memory through an SRC-1/mTORC2-dependent pathway in the hippocampus of female mice. J Steroid Biochem Mol Biol 174:96–113
Liu F, Day M, Muniz LC, Bitran D, Arias R, Revilla-Sanchez R, Grauer S, Zhang G, Kelley C, Pulito V, Sung A, Mervis RF, Navarra R, Hirst WD, Reinhart PH, Marquis KL, Moss SJ, Pangalos MN, Brandon NJ (2008) Activation of estrogen receptor-beta regulates hippocampal synaptic plasticity and improves memory. Nat Neurosci 11:334–343
Wang W, Le AA, Hou B, Lauterborn JC, Cox CD, Levin ER, Lynch G, Gall CM (2018) Memory-related synaptic plasticity is sexually dimorphic in rodent hippocampus. J Neurosci 38:7935–7951
Yoon BK, Chin J, Kim JW, Shin MH, Ahn S, Lee DY, Seo SW, Na DL (2018) Menopausal hormone therapy and mild cognitive impairment: a randomized, placebo-controlled trial. Menopause (New York, NY) 25:870–876
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
Guo H, Liu M, Zhang L, Wang L, Hou W, Ma Y, Ma Y (2020) The critical period for neuroprotection by estrogen replacement therapy and the potential underlying mechanisms. Curr Neuropharmacol 18:485–500
Yue X, Lu M, Lancaster T, Cao P, Honda S, Staufenbiel M, Harada N, Zhong Z, Shen Y, Li R (2005) Brain estrogen deficiency accelerates Abeta plaque formation in an Alzheimer’s disease animal model. Proc Natl Acad Sci USA 102:19198–19203
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 P45017alpha and P450 aromatase localized in neurons. Proc Natl Acad Sci USA 101:865–870
Zhang QG, Wang R, Tang H, Dong Y, Chan A, Sareddy GR, Vadlamudi RK, Brann DW (2014) Brain-derived estrogen exerts anti-inflammatory and neuroprotective actions in the rat hippocampus. Mol Cell Endocrinol 389:84–91
Azcoitia I, Yague JG, Garcia-Segura LM (2011) Estradiol synthesis within the human brain. Neuroscience 191:139–147
Butler HT, Warden DR, Hogervorst E, Ragoussis J, Smith AD, Lehmann DJ (2010) Association of the aromatase gene with Alzheimer’s disease in women. Neurosci Lett 468:202–206
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
Prange-Kiel J, Fester L, Zhou L, Lauke H, Carretero J, Rune GM (2006) Inhibition of hippocampal estrogen synthesis causes region-specific downregulation of synaptic protein expression in hippocampal neurons. Hippocampus 16:464–471
Grassi S, Tozzi A, Costa C, Tantucci M, Colcelli E, Scarduzio M, Calabresi P, Pettorossi VE (2011) Neural 17beta-estradiol facilitates long-term potentiation in the hippocampal CA1 region. Neuroscience 192:67–73
Prange-Kiel J, Fester L, Zhou L, Jarry H, Rune GM (2009) Estrus cyclicity of spinogenesis: underlying mechanisms. J Neural Transm 116:1417–1425
von Schassen C, Fester L, Prange-Kiel J, Lohse C, Huber C, Bottner M, Rune GM (2006) Oestrogen synthesis in the hippocampus: role in axon outgrowth. J Neuroendocrinol 18:847–856
Chamniansawat S, Chongthammakun S (2012) A priming role of local estrogen on exogenous estrogen-mediated synaptic plasticity and neuroprotection. Exp Mol Med 44:403–411
Koss WA, Frick KM (2019) Activation of androgen receptors protects intact male mice from memory impairments caused by aromatase inhibition. Horm Behav 111:96–104
Tuscher JJ, Szinte JS, Starrett JR, Krentzel AA, Fortress AM, Remage-Healey L, Frick KM (2016) Inhibition of local estrogen synthesis in the hippocampus impairs hippocampal memory consolidation in ovariectomized female mice. Horm Behav 83:60–67
Bailey DJ, Ma C, Soma KK, Saldanha CJ (2013) Inhibition of hippocampal aromatization impairs spatial memory performance in a male songbird. Endocrinology 154:4707–4714
Konkle AT, McCarthy MM (2011) Developmental time course of estradiol, testosterone, and dihydrotestosterone levels in discrete regions of male and female rat brain. Endocrinology 152:223–235
Mukai H, Kimoto T, Hojo Y, Kawato S, Murakami G, Higo S, Hatanaka Y, Ogiue-Ikeda M (2010) Modulation of synaptic plasticity by brain estrogen in the hippocampus. Biochem Biophys Acta 1800:1030–1044
Kato A, Hojo Y, Higo S, Komatsuzaki Y, Murakami G, Yoshino H, Uebayashi M, Kawato S (2013) Female hippocampal estrogens have a significant correlation with cyclic fluctuation of hippocampal spines. Frontiers Neural Circ 7:149
Rune GM, Lohse C, Prange-Kiel J, Fester L, Frotscher M (2006) Synaptic plasticity in the hippocampus: effects of estrogen from the gonads or hippocampus? Neurochem Res 31:145–155
Nelson BS, Black KL, Daniel JM (2016) Circulating estradiol regulates brain-derived estradiol via actions at gnrh receptors to impact memory in ovariectomized rats. eNeuro. https://doi.org/10.1523/ENEURO.0321-16.2016
Czajka-Oraniec I, Simpson ER (2010) Aromatase research and its clinical significance. Endokrynol Pol 61:126–134
Toda K, Hayashi Y, Okada T, Morohashi K, Saibara T (2005) Expression of the estrogen-inducible EGFP gene in aromatase-null mice reveals differential tissue responses to estrogenic compounds. Mol Cell Endocrinol 229:119–126
Murakami K, Hata S, Miki Y, Sasano H (2018) Aromatase in normal and diseased liver. Hormon Mol Biol Clin Invest. https://doi.org/10.1515/hmbci-2017-0081
Scott L, Feng J, Kiss T, Needle E, Atchison K, Kawabe TT, Milici AJ, Hajos-Korcsok E, Riddell D, Hajos M (2012) Age-dependent disruption in hippocampal theta oscillation in amyloid-beta overproducing transgenic mice. Neurobiol Aging 33(1481):e1413-1423
Sogorb-Esteve A, Garcia-Ayllon MS, Gobom J, Alom J, Zetterberg H, Blennow K, Saez-Valero J (2018) Levels of ADAM10 are reduced in Alzheimer’s disease CSF. J Neuroinflammation 15:213
Cai Z, Wang C, He W, Chen Y (2018) Berberine alleviates amyloid-beta pathology in the brain of APP/PS1 transgenic mice via inhibiting beta/gamma-secretases activity and enhancing alpha-secretases. Curr Alzheimer Res 15:1045–1052
Zhou L, Liu J, Dong D, Wei C, Wang R (2017) Dynamic alteration of neprilysin and endothelin-converting enzyme in age-dependent APPswe/PS1dE9 mouse model of Alzheimer’s disease. Am J Transl Res 9:184–196
Huang W, Zhu PJ, Zhang S, Zhou H, Stoica L, Galiano M, Krnjevic K, Roman G, Costa-Mattioli M (2013) mTORC2 controls actin polymerization required for consolidation of long-term memory. Nat Neurosci 16:441–448
Diao W, Chen W, Höger H, Pollak A, Lubec G (2008) Fluctuations of hippocampal neuronal protein levels over the estrous cycle in the rat. Neurochem Int 52:1002–1011
Yildirim M, Mapp O, Janssen W, Yin W, Morrison J (2008) Gore AJEn. Postpubertal decrease in hippocampal dendritic spines of female rats 210:339–348
Sun T, Liu Z, Liu M, Guo Y, Sun H, Zhao J, Lan Z, Lian B, Zhang J (2019) Hippocampus-specific Rictor knockdown inhibited 17beta-estradiol induced neuronal plasticity and spatial memory improvement in ovariectomized mice. Behav Brain Res 364:50–61
Zhao J, Bian C, Liu M, Zhao Y, Sun T, Xing F, Zhang J (2018) Orchiectomy and letrozole differentially regulate synaptic plasticity and spatial memory in a manner that is mediated by SRC-1 in the hippocampus of male mice. J Steroid Biochem Mol Biol 178:354–368
Tian H, Ding N, Guo M, Wang S, Wang Z, Liu H, Yang J, Li Y, Ren J, Jiang J, Li Z (2019) Analysis of learning and memory ability in an alzheimer’s disease mouse model using the morris water maze. JoVE. https://doi.org/10.3791/60055
Lichtenthaler SF (2012) Alpha-secretase cleavage of the amyloid precursor protein: proteolysis regulated by signaling pathways and protein trafficking. Curr Alzheimer Res 9:165–177
Tan JZA, Fourriere L, Wang J, Perez F, Boncompain G, Gleeson PA (2019) Distinct anterograde trafficking pathways of BACE1 and amyloid precursor protein from the TGN and the regulation of amyloid-beta production. Molecular biology of the cell:mbcE19090487
Yang W, Tian ZK, Yang HX, Feng ZJ, Sun JM, Jiang H, Cheng C, Ming QL, Liu CM (2019) Fisetin improves lead-induced neuroinflammation, apoptosis and synaptic dysfunction in mice associated with the AMPK/SIRT1 and autophagy pathway. Food Chem Toxicol 134:110824
Vallejo D, Codocedo JF, Inestrosa NC (2017) Posttranslational Modifications Regulate the Postsynaptic Localization of PSD-95. Mol Neurobiol 54:1759–1776
Lin CH, Lee EH (2012) JNK1 inhibits GluR1 expression and GluR1-mediated calcium influx through phosphorylation and stabilization of Hes-1. J Neurosci 32:1826–1846
Chidambaram SB, Rathipriya AG, Bolla SR, Bhat A, Ray B, Mahalakshmi AM, Manivasagam T, Thenmozhi AJ, Essa MM, Guillemin GJ, Chandra R, Sakharkar MK (2019) Dendritic spines: revisiting the physiological role. Prog Neuropsychopharmacol Biol Psychiatry 92:161–193
Bian C, Zhu H, Zhao Y, Cai W, Zhang J (2014) Intriguing roles of hippocampus-synthesized 17beta-estradiol in the modulation of hippocampal synaptic plasticity. J Mol Neurosci 54:271–281
Lu Y, Sareddy GR, Wang J, Wang R, Li Y, Dong Y, Zhang Q, Liu J, O’Connor JC, Xu J, Vadlamudi RK, Brann DW (2019) Neuron-derived estrogen regulates synaptic plasticity and memory. J Neurosci 39:2792–2809
Baumgartner NE, Grissom EM, Pollard KJ, McQuillen SM, Daniel JM (2019) Neuroestrogen-dependent transcriptional activity in the brains of ERE-luciferase reporter mice following short- and long-term ovariectomy. eNeuro. https://doi.org/10.1523/ENEURO.0275-19.2019
Vedder LC, Bredemann TM, McMahon LL (2014) Estradiol replacement extends the window of opportunity for hippocampal function. Neurobiol Aging 35:2183–2192
Bredemann TM, McMahon LL (2014) 17beta Estradiol increases resilience and improves hippocampal synaptic function in helpless ovariectomized rats. Psychoneuroendocrinology 42:77–88
Anukulthanakorn K, Malaivijitnond S, Kitahashi T, Jaroenporn S, Parhar I (2013) Molecular events during the induction of neurodegeneration and memory loss in estrogen-deficient rats. Gen Comp Endocrinol 181:316–323
Yang HQ, Sun ZK, Jiang QH, Shang Q, Xu J (2009) Effect of estrogen-depletion and 17beta-estradiol replacement therapy upon rat hippocampus beta-amyloid generation. Zhonghua yi xue za zhi 89:2658–2661
Hou Y, Bao XQ, Wei HL, Luo Y, Liu GT (2011) Long-term deprivation of gonadal hormone accelerates brain aging in mice. Neurol Res 33:43–49
Fukuzaki E, Takuma K, Himeno Y, Yoshida S, Funatsu Y, Kitahara Y, Mizoguchi H, Ibi D, Koike K, Inoue M, Yamada K (2008) Enhanced activity of hippocampal BACE1 in a mouse model of postmenopausal memory deficits. Neurosci Lett 433:141–145
Jackson J, Jambrina E, Li J, Marston H, Menzies F, Phillips K, Gilmour G (2019) Targeting the synapse in Alzheimer’s disease. Frontiers Neurosci 13:735
Dominguez-Iturza N, Calvo M, Benoist M, Esteban JA, Morales M (2016) Hippocampal dendritic spines are segregated depending on their actin polymerization. Neural Plasticity 2016:2819107
Hlushchenko I, Koskinen M, Hotulainen P (2016) Dendritic spine actin dynamics in neuronal maturation and synaptic plasticity. Cytoskeleton (Hoboken) 73:435–441
Kevenaar JT, Hoogenraad CC (2015) The axonal cytoskeleton: from organization to function. Front Mol Neurosci 8:44
Bian C, Zhu K, Yang L, Lin S, Li S, Su B, Zhang J (2012) Gonadectomy differentially regulates steroid receptor coactivator-1 and synaptic proteins in the hippocampus of adult female and male C57BL/6 mice. Synapse 66:849–857
Zhang D, Zhang J, Bian C, Deng Q (2010) Postnatal and ovariectomic regulation of postsynaptic density protein-95 in the hippocampus of female Sprague-Dawley rats. Synapse 64:875–878
Liu M, Huangfu X, Zhao Y, Zhang D, Zhang J (2015) Steroid receptor coactivator-1 mediates letrozole induced downregulation of postsynaptic protein PSD-95 in the hippocampus of adult female rats. J Steroid Biochem Mol Biol 154:168–175
Bayer J, Rune G, Schultz H, Tobia MJ, Mebes I, Katzler O, Sommer T (2015) The effect of estrogen synthesis inhibition on hippocampal memory. Psychoneuroendocrinology 56:213–225
Leranth C, Hajszan T, MacLusky NJ (2004) Androgens increase spine synapse density in the CA1 hippocampal subfield of ovariectomized female rats. J Neurosci 24:495–499
Prange-Kiel J, Rune GM (2006) Direct and indirect effects of estrogen on rat hippocampus. Neuroscience 138:765–772
Oberlander JG, Schlinger BA, Clayton NS, Saldanha CJ (2004) Neural aromatization accelerates the acquisition of spatial memory via an influence on the songbird hippocampus. Horm Behav 45:250–258
Rune GM, Frotscher M (2005) Neurosteroid synthesis in the hippocampus: role in synaptic plasticity. Neuroscience 136:833–842
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This work was supported by the grant from the Development and Regeneration Key Laboratory of Sichuan Province (SYS18-02), Postdoctoral Research Foundation of China (2019M653976) and Natural Science Foundation of Chongqing (cstc2019jcyj-msxmX0255).
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Lan, Z., Meng, Z., Lian, B. et al. Hippocampal Aromatase Knockdown Aggravates Ovariectomy‐Induced Spatial Memory Impairment, Aβ Accumulation and Neural Plasticity Deficiency in Adult Female Mice. Neurochem Res 46, 1188–1202 (2021). https://doi.org/10.1007/s11064-021-03258-5
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DOI: https://doi.org/10.1007/s11064-021-03258-5