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Effects of estradiol supplementation on the brain transcriptome of old rhesus macaques maintained on an obesogenic diet

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Abstract

Obesity, the cessation of ovarian steroids with menopause, and age are risk factors for mood disorders, dementia, and Alzheimer’s disease (AD). However, immediate hormone therapy (HT) after menopause may have beneficial effects in different brain regions involved in memory and cognition. To more closely replicate the age, endocrine, and metabolic environment of obese postmenopausal women, either on or off HT, middle-aged female rhesus macaques were ovariectomized/hysterectomized (OvH) and maintained on a high-fat, high-sugar, obesogenic Western-style diet (WSD) for 30 months; half of the animals received HT immediately after OvH and half served as placebo controls. RNAseq of the occipital (OC) and prefrontal cortex (PFC), hippocampus (HIP), and amygdala (AMG) identified 293, 379, 505, and 4993 differentially expressed genes (DEGs), respectively. Pathway enrichment analysis identified an activation of neuroinflammation in OC and HIP, but an inhibition in the AMG with HT. Synaptogenesis, circadian rhythm, mitochondrial dysfunction, mTOR, glutamate, serotonin, GABA, dopamine, epinephrine/norepinephrine, glucocorticoid receptor signaling, neuronal NOS, and amyloid processing were exclusively enriched in AMG. As compared to the placebo control group, most of these signaling pathways are downregulated after HT, suggesting a protective effect of HT in OvH females under a WSD. Overall, our results suggest that a chronic obesogenic diet may induce a wide range of alterations in multiple signaling pathways that are linked to age-associated brain pathology and dementia. In these individuals, HT seems to have a protective effect against neuroinflammation, amyloid beta depositions, and tau tangle formation.

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Data availability

All relevant data was provided upon the submission of this manuscript. RNAseq data is deposited in GSE174153.

Code availability

Code is available upon request.

References

  1. Gilardi KV, Shideler SE, Valverde CR, Roberts JA, Lasley BL. Characterization of the onset of menopause in the rhesus macaque. Biol Reprod. 1997;57(2):335–40.

    Article  CAS  PubMed  Google Scholar 

  2. Downs JL, Urbanski HF. Neuroendocrine changes in the aging reproductive axis of female rhesus macaques (Macaca mulatta). Biol Reprod. 2006;75(4):539–46.

    Article  CAS  PubMed  Google Scholar 

  3. Kozakowski J, Gietka-Czernel M, Leszczynska D, Majos A. Obesity in menopause - our negligence or an unfortunate inevitability? Prz Menopauzalny. 2017;16(2):61–5.

    PubMed  PubMed Central  Google Scholar 

  4. Luna SL, Brown DI, Kohama SG, Urbanski HF. Lack of effect of short-term DHEA supplementation on the perimenopausal ovarydagger. Biol Reprod. 2020;103(6):1209–16.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Bacon ER, Mishra A, Wang Y, Desai MK, Yin F, Brinton RD. Neuroendocrine aging precedes perimenopause and is regulated by DNA methylation. Neurobiol Aging. 2019;74:213–24.

    Article  CAS  PubMed  Google Scholar 

  6. Downs JL, Wise PM. The role of the brain in female reproductive aging. Mol Cell Endocrinol. 2009;299(1):32–8.

    Article  CAS  PubMed  Google Scholar 

  7. Finch CE. The menopause and aging, a comparative perspective. J Steroid Biochem Mol Biol. 2014;142:132–41.

    Article  CAS  PubMed  Google Scholar 

  8. Cohen LS, Soares CN, Joffe H. Diagnosis and management of mood disorders during the menopausal transition. Am J Med. 2005;118(Suppl 12B):93–7.

    Article  PubMed  Google Scholar 

  9. Verhaeghe J. Menopause care for obese and diabetic women. Facts Views Vis Obgyn. 2009;1(2):142–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Thaung Zaw JJ, Howe PRC, Wong RHX. Postmenopausal health interventions: time to move on from the Women's Health Initiative? Ageing Res Rev. 2018;48:79–86.

    Article  PubMed  Google Scholar 

  11. Manson JE, Aragaki AK, Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, et al. Menopausal hormone therapy and long-term all-cause and cause-specific mortality: the Women's Health Initiative randomized trials. JAMA. 2017;318(10):927–38.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Chlebowski RT, Anderson G, Pettinger M, Lane D, Langer RD, Gilligan MA, et al. Estrogen plus progestin and breast cancer detection by means of mammography and breast biopsy. Arch Intern Med. 2008;168(4):370–377; quiz 45.

  13. Chlebowski RT, Anderson GL, Gass M, Lane DS, Aragaki AK, Kuller LH, et al. Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA. 2010;304(15):1684–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Khadilkar SS. Post-reproductive health: window of opportunity for preventing comorbidities. J Obstet Gynaecol India. 2019;69(1):1–5.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Davey DA. Menopausal hormone therapy: a better and safer future. Climacteric. 2018;21(5):454–61.

    Article  CAS  PubMed  Google Scholar 

  16. Scheyer O, Rahman A, Hristov H, Berkowitz C, Isaacson RS, Diaz Brinton R, et al. Female sex and Alzheimer's risk: the menopause connection. J Prev Alzheimers Dis. 2018;5(4):225–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Espeland MA, Rapp SR, Shumaker SA, Brunner R, Manson JE, Sherwin BB, et al. Conjugated equine estrogens and global cognitive function in postmenopausal women: Women's Health Initiative memory study. JAMA. 2004;291(24):2959–68.

    Article  CAS  PubMed  Google Scholar 

  18. Kohama SG, Renner L, Landauer N, Weiss AR, Urbanski HF, Park B, et al. Effect of ovarian hormone therapy on cognition in the aged female rhesus macaque. J Neurosci. 2016;36(40):10416–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Paganini-Hill A, Henderson VW. Estrogen deficiency and risk of Alzheimer's disease in women. Am J Epidemiol. 1994;140(3):256–61.

    Article  CAS  PubMed  Google Scholar 

  20. Rapp SR, Espeland MA, Shumaker SA, Henderson VW, Brunner RL, Manson JE, et al. Effect of estrogen plus progestin on global cognitive function in postmenopausal women: the Women's Health Initiative memory study: a randomized controlled trial. JAMA. 2003;289(20):2663–72.

    Article  CAS  PubMed  Google Scholar 

  21. Rocca WA, Grossardt BR, Shuster LT. Oophorectomy, estrogen, and dementia: a 2014 update. Mol Cell Endocrinol. 2014;389(1–2):7–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Shao H, Breitner JC, Whitmer RA, Wang J, Hayden K, Wengreen H, et al. Hormone therapy and Alzheimer disease dementia: new findings from the Cache County study. Neurology. 2012;79(18):1846–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Coleman K, Robertson ND, Maier A, Bethea CL. Effects of immediate or delayed estradiol on behavior in old menopausal macaques on obesogenic diet. J Obes. 2018;2018:1810275.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Baxter MG, Santistevan AC, Bliss-Moreau E, Morrison JH. Timing of cyclic estradiol treatment differentially affects cognition in aged female rhesus monkeys. Behav Neurosci. 2018;132(4):213–23.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Zimmerman B, Kundu P, Liu Z, Urbanski HF, Kroenke CD, Kohama SG, et al. Longitudinal effects of immediate and delayed estradiol on cognitive performance in a spatial maze and hippocampal volume in menopausal macaques under an obesogenic diet. Front Neurol. 2020;11:539.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Craig M. Hales MDC, Cheryl D. Fryar, and Cynthia L. Ogden. Prevalence of obesity and severe obesity among adults: United States, 2017–2018. https://www.cdc.gov/nchs/products/databriefs/db360htm. Accessed 28 September 2020.

  27. Kopp W. How Western diet and lifestyle drive the pandemic of obesity and civilization diseases. Diabetes Metab Syndr Obes. 2019;12:2221–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Jayaraman A, Pike CJ. Alzheimer's disease and type 2 diabetes: multiple mechanisms contribute to interactions. Curr Diab Rep. 2014;14(4):476.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Beam CR, Kaneshiro C, Jang JY, Reynolds CA, Pedersen NL, Gatz M. Differences between women and men in incidence rates of dementia and Alzheimer's disease. J Alzheimers Dis. 2018;64(4):1077–83.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Laws KR, Irvine K, Gale TM. Sex differences in Alzheimer's disease. Curr Opin Psychiatry. 2018;31(2):133–9.

    Article  PubMed  Google Scholar 

  31. Podcasy JL, Epperson CN. Considering sex and gender in Alzheimer disease and other dementias. Dialogues Clin Neurosci. 2016;18(4):437–46.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Kaufman JM, Lapauw B, Mahmoud A, T'Sjoen G, Huhtaniemi IT. Aging and the male reproductive system. Endocr Rev. 2019;40(4):906–72.

    Article  PubMed  Google Scholar 

  33. Diseases NIoDaDaK. Overweigth and obesity statistics. National Institute of Diabeter and Digestive and Kidney Diseases. 2020.

  34. Bethea CL, Mueller K, Reddy AP, Kohama SG, Urbanski HF. Effects of obesogenic diet and estradiol on dorsal raphe gene expression in old female macaques. PLoS One. 2017;12(6):e0178788.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Rehman A, Al Khalili Y. Neuroanatomy, Occipital Lobe. StatPearls. Treasure Island (FL) 2021.

  36. Stufflebeam SM, Rosen BR. Mapping cognitive function. Neuroimaging Clin N Am. 2007;17(4):469–484, viii-ix.

  37. Funahashi S, Andreau JM. Prefrontal cortex and neural mechanisms of executive function. J Physiol Paris. 2013;107(6):471–82.

    Article  PubMed  Google Scholar 

  38. Anand KS, Dhikav V. Hippocampus in health and disease: an overview. Ann Indian Acad Neurol. 2012;15(4):239–46.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Bonnet L, Comte A, Tatu L, Millot JL, Moulin T. Medeiros de Bustos E. the role of the amygdala in the perception of positive emotions: an "intensity detector". Front Behav Neurosci. 2015;9:178.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Ressler KJ. Amygdala activity, fear, and anxiety: modulation by stress. Biol Psychiatry. 2010;67(12):1117–9.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Yavas E, Gonzalez S, Fanselow MS. Interactions between the hippocampus, prefrontal cortex, and amygdala support complex learning and memory. Faculty Rev. 2019;8:F1000. https://doi.org/10.12688/f1000research.19317.1.

  42. Walf AA, Frye CA. A review and update of mechanisms of estrogen in the hippocampus and amygdala for anxiety and depression behavior. Neuropsychopharmacology. 2006;31(6):1097–111.

    Article  CAS  PubMed  Google Scholar 

  43. Colman DJK, J.W. Methods in aging research. Boca Raton: CRC Press; 1999.

    Google Scholar 

  44. Purnell JQ, Urbanski HF, Kievit P, Roberts CT, Bethea CL. Estradiol replacement timing and obesogenic diet effects on body composition and metabolism in postmenopausal macaques. Endocrinology. 2019;160(4):899–914.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Andrews, S. ASTQC. A quality control tool for high throughput sequence data. 2010. https://www.bibsonomy.org/bibtex/2b6052877491828ab53d3449be9b293b3/ozborn.

  46. Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29(1):15–21.

    Article  CAS  PubMed  Google Scholar 

  47. Robinson MD, McCarthy DJ, Smyth GK. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010;26(1):139–40.

    Article  CAS  PubMed  Google Scholar 

  48. Chen Y, Lun AT, Smyth GK. From reads to genes to pathways: differential expression analysis of RNA-Seq experiments using Rsubread and the edgeR quasi-likelihood pipeline. F1000Res. 2016;5:1438.

    PubMed  PubMed Central  Google Scholar 

  49. McKenzie AT, Wang M, Hauberg ME, Fullard JF, Kozlenkov A, Keenan A, et al. Brain cell type specific gene expression and co-expression network architectures. Sci Rep. 2018;8(1):8868.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Yu G, Wang LG, Han Y, He QY. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS. 2012;16(5):284–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Rutter LC, D. bigPint: big multivariate data plotted interactively. R package version 1.4.0. https://github.com/lindsayrutter/bigPint. Accessed 28 September 2020.

  52. Blighe K, Lun, A. PCAtools: PCAtools: everything principal components analysis. R package version 2.0.0. https://github.com/kevinblighe/PCAtools. Accessed 28 September 2020.

  53. Cervera-Juanes R, Wilhem LJ, Park B, Lee R, Locke J, Helms C, Gonzales S, Wand G, Jones SR, Grant KA, Ferguson B. MAOA expression predicts vulnerability for alcohol use. Mol Psychiatry. 2016;21(4):472–9. https://doi.org/10.1007/s11357-021-00453-8.

  54. Abraham CR, Selkoe DJ, Potter H. Immunochemical identification of the serine protease inhibitor alpha 1-antichymotrypsin in the brain amyloid deposits of Alzheimer's disease. Cell. 1988;52(4):487–501.

    Article  CAS  PubMed  Google Scholar 

  55. Ayana R, Singh S, Pati S. Deconvolution of human brain cell type transcriptomes unraveled microglia-specific potential biomarkers. Front Neurol. 2018;9:266.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Goodman T, Nayar SG, Clare S, Mikolajczak M, Rice R, Mansour S, Bellusci S, Hajihosseini MK. Fibroblast growth factor 10 is a negative regulator of postnatal neurogenesis in the mouse hypothalamus. Development. 2020;147(13):dev180950. https://doi.org/10.1242/dev.180950.

  57. Haan N, Goodman T, Najdi-Samiei A, Stratford CM, Rice R, El Agha E, et al. Fgf10-expressing tanycytes add new neurons to the appetite/energy-balance regulating centers of the postnatal and adult hypothalamus. J Neurosci. 2013;33(14):6170–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Osterlund MK, Hurd YL. Estrogen receptors in the human forebrain and the relation to neuropsychiatric disorders. Prog Neurobiol. 2001;64(3):251–67.

    Article  CAS  PubMed  Google Scholar 

  59. Freeman LR, Haley-Zitlin V, Rosenberger DS, Granholm AC. Damaging effects of a high-fat diet to the brain and cognition: a review of proposed mechanisms. Nutr Neurosci. 2014;17(6):241–51.

    Article  PubMed  Google Scholar 

  60. Scott SA, DeKosky ST, Scheff SW. Volumetric atrophy of the amygdala in Alzheimer's disease: quantitative serial reconstruction. Neurology. 1991;41(3):351–6.

    Article  CAS  PubMed  Google Scholar 

  61. Vereecken TH, Vogels OJ, Nieuwenhuys R. Neuron loss and shrinkage in the amygdala in Alzheimer's disease. Neurobiol Aging. 1994;15(1):45–54.

    Article  CAS  PubMed  Google Scholar 

  62. Uno H. The incidence of senile plaques and multiple infarction in aged macaque brain. Neurobiol Aging. 1993;14(6):673–4.

    Article  CAS  PubMed  Google Scholar 

  63. Boada M, Antunez C, Lopez-Arrieta J, Caruz A, Moreno-Rey C, Ramirez-Lorca R, et al. Estrogen receptor alpha gene variants are associated with Alzheimer's disease. Neurobiol Aging. 2012;33(1):198 e15–24.

  64. Janicki SC, Park N, Cheng R, Clark LN, Lee JH, Schupf N. Estrogen receptor alpha variants affect age at onset of Alzheimer's disease in a multiethnic female cohort. Dement Geriatr Cogn Disord. 2014;38(3–4):200–13.

    Article  CAS  PubMed  Google Scholar 

  65. Sundermann EE, Maki PM, Bishop JR. A review of estrogen receptor alpha gene (ESR1) polymorphisms, mood, and cognition. Menopause. 2010;17(4):874–86.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Shifren JL, Gass LS. The North American Menopause Society recommendations for clinical care of midlife women. J North Am Menopause Soc 2014;21(10):1–25.

  67. Aguilar-Valles A, Inoue W, Rummel C, Luheshi GN. Obesity, adipokines and neuroinflammation. Neuropharmacology. 2015;96(Pt A):124–34.

    Article  CAS  PubMed  Google Scholar 

  68. Thaler JP, Schwartz MW. Minireview: inflammation and obesity pathogenesis: the hypothalamus heats up. Endocrinology. 2010;151(9):4109–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Thaler JP, Yi CX, Schur EA, Guyenet SJ, Hwang BH, Dietrich MO, et al. Obesity is associated with hypothalamic injury in rodents and humans. J Clin Invest. 2012;122(1):153–62.

    Article  CAS  PubMed  Google Scholar 

  70. Vegeto E, Benedusi V, Maggi A. Estrogen anti-inflammatory activity in brain: a therapeutic opportunity for menopause and neurodegenerative diseases. Front Neuroendocrinol. 2008;29(4):507–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Moser VA, Pike CJ. Obesity and sex interact in the regulation of Alzheimer's disease. Neurosci Biobehav Rev. 2016;67:102–18.

    Article  CAS  PubMed  Google Scholar 

  72. Alford S, Patel D, Perakakis N, Mantzoros CS. Obesity as a risk factor for Alzheimer's disease: weighing the evidence. Obes Rev. 2018;19(2):269–80.

    Article  CAS  PubMed  Google Scholar 

  73. Naderali EK, Ratcliffe SH, Dale MC. Obesity and Alzheimer's disease: a link between body weight and cognitive function in old age. Am J Alzheimers Dis Other Demen. 2009 Dec-2010;24(6):445–9.

  74. Herculano B, Tamura M, Ohba A, Shimatani M, Kutsuna N, Hisatsune T. beta-alanyl-L-histidine rescues cognitive deficits caused by feeding a high fat diet in a transgenic mouse model of Alzheimer's disease. J Alzheimers Dis. 2013;33(4):983–97.

    Article  CAS  PubMed  Google Scholar 

  75. Julien C, Tremblay C, Phivilay A, Berthiaume L, Emond V, Julien P, et al. High-fat diet aggravates amyloid-beta and tau pathologies in the 3xTg-AD mouse model. Neurobiol Aging. 2010;31(9):1516–31.

    Article  CAS  PubMed  Google Scholar 

  76. Orr ME, Garbarino VR, Salinas A, Buffenstein R. Sustained high levels of neuroprotective, high molecular weight, phosphorylated tau in the longest-lived rodent. Neurobiol Aging. 2015;36(3):1496–504.

    Article  CAS  PubMed  Google Scholar 

  77. Takalo M, Haapasalo A, Martiskainen H, Kurkinen KM, Koivisto H, Miettinen P, et al. High-fat diet increases tau expression in the brain of T2DM and AD mice independently of peripheral metabolic status. J Nutr Biochem. 2014;25(6):634–41.

    Article  CAS  PubMed  Google Scholar 

  78. Barron AM, Rosario ER, Elteriefi R, Pike CJ. Sex-specific effects of high fat diet on indices of metabolic syndrome in 3xTg-AD mice: implications for Alzheimer's disease. PLoS One. 2013;8(10):e78554.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. O'Brien PD, Hinder LM, Callaghan BC, Feldman EL. Neurological consequences of obesity. Lancet Neurol. 2017;16(6):465–77.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Estrada CM, Ghisays V, Nguyen ET, Caldwell JL, Streicher J, Solomon MB. Estrogen signaling in the medial amygdala decreases emotional stress responses and obesity in ovariectomized rats. Horm Behav. 2018;98:33–44.

    Article  CAS  PubMed  Google Scholar 

  81. Figlewicz DP, MacDonald Naleid A, Sipols AJ. Modulation of food reward by adiposity signals. Physiol Behav. 2007;91(5):473–8.

    Article  CAS  PubMed  Google Scholar 

  82. Will MJ, Franzblau EB, Kelley AE. The amygdala is critical for opioid-mediated binge eating of fat. Neuroreport. 2004;15(12):1857–60.

    Article  CAS  PubMed  Google Scholar 

  83. Boghossian S, Lemmon K, Park M, York DA. High-fat diets induce a rapid loss of the insulin anorectic response in the amygdala. Am J Physiol Regul Integr Comp Physiol. 2009;297(5):R1302–11.

    Article  CAS  PubMed  Google Scholar 

  84. Urbanski HF, Mueller K, Bethea CL. Effect of an obesogenic diet on circadian activity and serum hormones in old monkeys. Endocr Connect. 2017;6(6):380–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Lloret A, Monllor P, Esteve D, Cervera-Ferri A, Lloret MA. Obesity as a risk factor for Alzheimer's disease: implication of leptin and glutamate. Front Neurosci. 2019;13:508.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Ong WY, Tanaka K, Dawe GS, Ittner LM, Farooqui AA. Slow excitotoxicity in Alzheimer's disease. J Alzheimers Dis. 2013;35(4):643–68.

    Article  PubMed  Google Scholar 

  87. Kim C, Kong S, Laughlin GA, Golden SH, Mather KJ, Nan B, et al. Reductions in glucose among postmenopausal women who use and do not use estrogen therapy. Menopause. 2013;20(4):393–400.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Morinaga A, Hirohata M, Ono K, Yamada M. Estrogen has anti-amyloidogenic effects on Alzheimer's beta-amyloid fibrils in vitro. Biochem Biophys Res Commun. 2007;359(3):697–702.

    Article  CAS  PubMed  Google Scholar 

  89. Pike CJ, Carroll JC, Rosario ER, Barron AM. Protective actions of sex steroid hormones in Alzheimer's disease. Front Neuroendocrinol. 2009;30(2):239–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Yue X, Lu M, Lancaster T, Cao P, Honda S, Staufenbiel M, et al. Brain estrogen deficiency accelerates Abeta plaque formation in an Alzheimer's disease animal model. Proc Natl Acad Sci U S A. 2005;102(52):19198–203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Guglielmotto M, Manassero G, Vasciaveo V, Venezia M, Tabaton M, Tamagno E. Estrogens inhibit amyloid-beta-mediated paired helical filament-like conformation of tau through antioxidant activity and miRNA 218 regulation in hTau mice. J Alzheimers Dis. 2020;77(3):1339–51.

    Article  CAS  PubMed  Google Scholar 

  92. Hara Y, Crimins JL, Puri R, Wang ACJ, Motley SE, Yuk F, et al. Estrogen alters the synaptic distribution of phospho-GluN2B in the dorsolateral prefrontal cortex while promoting working memory in aged rhesus monkeys. Neuroscience. 2018;394:303–15.

    Article  CAS  PubMed  Google Scholar 

  93. Marrocco J, McEwen BS. Sex in the brain: hormones and sex differences. Dialogues Clin Neurosci. 2016;18(4):373–83.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Xu H, Wang R, Zhang YW, Zhang X. Estrogen, beta-amyloid metabolism/trafficking, and Alzheimer's disease. Ann N Y Acad Sci. 2006;1089:324–42.

    Article  CAS  PubMed  Google Scholar 

  95. Gao YL, Wang N, Sun FR, Cao XP, Zhang W, Yu JT. Tau in neurodegenerative disease. Ann Transl Med. 2018;6(10):175.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Ferreira A. Calpain dysregulation in Alzheimer's disease. ISRN Biochem. 2012;2012:728571.

    Article  PubMed  PubMed Central  Google Scholar 

  97. Carlyle BC, Nairn AC, Wang M, Yang Y, Jin LE, Simen AA, et al. cAMP-PKA phosphorylation of tau confers risk for degeneration in aging association cortex. Proc Natl Acad Sci U S A. 2014;111(13):5036–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Chen C, Gu J, Basurto-Islas G, Jin N, Wu F, Gong CX, et al. Up-regulation of casein kinase 1epsilon is involved in tau pathogenesis in Alzheimer's disease. Sci Rep. 2017;7(1):13478.

    Article  PubMed  PubMed Central  Google Scholar 

  99. Gabbouj S, Ryhanen S, Marttinen M, Wittrahm R, Takalo M, Kemppainen S, et al. Altered insulin signaling in Alzheimer's disease brain - special emphasis on PI3K-Akt pathway. Front Neurosci. 2019;13:629.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Lee JK, Kim N-J. Recent advances in the inhibition of p38 MAPK as a potential strategy for the treatment of Alzheimer's disease. Molecules. 2017;22(8):1287. https://doi.org/10.3390/molecules22081287.

  101. Llorens-Martin M, Jurado J, Hernandez F, Avila J. GSK-3beta, a pivotal kinase in Alzheimer disease. Front Mol Neurosci. 2014;7:46.

    CAS  PubMed  Google Scholar 

  102. Lund H, Gustafsson E, Svensson A, Nilsson M, Berg M, Sunnemark D, et al. MARK4 and MARK3 associate with early tau phosphorylation in Alzheimer's disease granulovacuolar degeneration bodies. Acta Neuropathol Commun. 2014;2:22.

    Article  PubMed  PubMed Central  Google Scholar 

  103. Wilkaniec A, Gassowska-Dobrowolska M, Strawski M, Adamczyk A, Czapski GA. Inhibition of cyclin-dependent kinase 5 affects early neuroinflammatory signalling in murine model of amyloid beta toxicity. J Neuroinflammation. 2018;15(1):1.

    Article  PubMed  PubMed Central  Google Scholar 

  104. Manzine PR, Barham EJ, Vale Fde A, Selistre-de-Araujo HS, Iost Pavarini SC, Cominetti MR. Correlation between mini-mental state examination and platelet ADAM10 expression in Alzheimer's disease. J Alzheimers Dis. 2013;36(2):253–60.

    Article  CAS  PubMed  Google Scholar 

  105. Manzine PR, de Franca Bram JM, Barham EJ, do Vale Fde A, Selistre-de-Araujo HS, Cominetti MR, et al. ADAM10 as a biomarker for Alzheimer's disease: a study with Brazilian elderly. Dement Geriatr Cogn Disord 2013;35(1–2):58–66.

  106. Sogorb-Esteve A, Garcia-Ayllon MS, Gobom J, Alom J, Zetterberg H, Blennow K, et al. Levels of ADAM10 are reduced in Alzheimer's disease CSF. J Neuroinflammation. 2018;15(1):213.

    Article  PubMed  PubMed Central  Google Scholar 

  107. Brewer GJ, Reichensperger JD, Brinton RD. Prevention of age-related dysregulation of calcium dynamics by estrogen in neurons. Neurobiol Aging. 2006;27(2):306–17.

    Article  CAS  PubMed  Google Scholar 

  108. Brinton RD, Chen S, Montoya M, Hsieh D, Minaya J. 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. 2000;34(Suppl 2):S35–52.

    Article  CAS  PubMed  Google Scholar 

  109. Green PS, Gridley KE, Simpkins JW. Estradiol protects against beta-amyloid (25-35)-induced toxicity in SK-N-SH human neuroblastoma cells. Neurosci Lett. 1996;218(3):165–8.

    Article  CAS  PubMed  Google Scholar 

  110. Nilsen J, Chen S, Irwin RW, Iwamoto S, Brinton RD. Estrogen protects neuronal cells from amyloid beta-induced apoptosis via regulation of mitochondrial proteins and function. BMC Neurosci. 2006;7:74.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Carlos Aylwin Ramirez for his assistance in qPCR analysis.

Funding

This work was supported by National Institutes of Health grants AG-029612, AG-062220, OD-011092, and OD-011895.

Author information

Authors and Affiliations

  1. Division of Genetics, Oregon National Primate Research Center, 505 NW 185th Avenue, Beaverton, OR, 97006, USA

    Rita Cervera-Juanes, Priscila Darakjian & Megan Ball

  2. Division of Neuroscience, Oregon National Primate Research Center, 505 NW 185th Avenue, Beaverton, OR, 97006, USA

    Steven G. Kohama & Henryk F. Urbanski

  3. Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, 97239, USA

    Henryk F. Urbanski

Authors
  1. Rita Cervera-Juanes
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  2. Priscila Darakjian
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  3. Megan Ball
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  4. Steven G. Kohama
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  5. Henryk F. Urbanski
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Contributions

HFU, SGK, and RPCJ were responsible for the study concept and design. HFU and SGK contributed to the acquisition of animal data. RPCJ performed the RNA extractions and RNAseq libraries. PD conducted the bioinformatic analysis. MB performed the qPCR analysis. HFU, SGK, and RPCJ contributed data analysis and interpretation of findings. HFU, SGK, and RPCJ drafted the manuscript. All authors critically reviewed content and approved final version for publication.

Corresponding author

Correspondence to Rita Cervera-Juanes.

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Conflict of interest

The authors declare no competing interests.

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Supplementary Information

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Ward plots showing clusters of genes showing similar patterns of differential expression between groups (OvH vs OvH-HT) across tissues: OC (a, b), PCF (c, d), HIP (e, f) and AMG (g, h). The number of genes included in each cluster is shown above each plot, and the samples within each group are shown in the x axis (PNG 2126 kb)

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Cervera-Juanes, R., Darakjian, P., Ball, M. et al. Effects of estradiol supplementation on the brain transcriptome of old rhesus macaques maintained on an obesogenic diet. GeroScience 44, 229–252 (2022). https://doi.org/10.1007/s11357-021-00453-8

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  • DOI: https://doi.org/10.1007/s11357-021-00453-8

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