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Full Length Article | Open Access

Estrogen deficiency exacerbates learning and memory deficits associated with glucose metabolism disorder in APP/PS1 double transgenic female mice

Min Luoa,b,1, Qinghua Zenga,c,1, Kai Jiangd, Yueyang Zhaoa, Zhimin Longa,c, Yexiang Dua, Kejian Wanga,c( ), Guiqiong Hea,c( )
Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing 400016, PR China
Department of Pathology, Suining Municipal Hospital of TCM, Suining, Sichuan 629000, PR China
Department of Anatomy, Chongqing Medical University, Chongqing 400016, PR China
Department of Gastroenterology, Suining Central Hospital, Suining, Sichuan 629000, PR China

Peer review under responsibility of Chongqing Medical University.

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Abstract

Alterations in glucose metabolism occur in the brain in the early stage of Alzheimer's disease (AD), and menopausal women have more severe metabolic dysfunction and are more prone to dementia than men. Although estrogen deficiency-induced changes in glucose metabolism have been previously studied in animal models, their molecular mechanisms in AD remain elusive. To investigate this issue, double transgenic (APP/PS1) female mice were subjected to bilateral ovariectomy at 3 months of age and were sacrificed 1 week, 1 month and 3 months after surgery to simulate early, middle and late postmenopause, respectively. Our analysis demonstrated that estrogen deficiency exacerbates learning and memory deficits in this mouse model of postmenopause. Estrogen deficiency impairs the function of mitochondria in glucose metabolism. It is possible that the occurrence of AD is associated with the aberrant mitochondrial ERβ-mediated IGF-1/IGF-1R/GSK-3β signaling pathway. In this study, we established a potential mechanism for the increased risk of AD in postmenopausal women and proposed a therapeutic target for AD due to postmenopause.

Keywords

Alzheimer's diseaseMitochondriaIGF-1Estrogen deficiencyGlucose metabolism disorderGSK-3β

References

1

Grøntvedt GR, Schröder TN, Sando SB, White L, Bråthen G, Doeller CF. Alzheimer's disease. Curr Biol. 2018;28(11): R645-R649.
Crossref Google Scholar
2

Carrillo MC, Dean RA, Nicolas F, et al. Revisiting the framework of the national Institute on aging-Alzheimer's association diagnostic criteria. Alzheimers Dement. 2013;9(5): 594-601.
Crossref Google Scholar
3

Ameen-Ali KE, Wharton SB, Simpson JE, Heath PR, Sharp P, Berwick J. Review: neuropathology and behavioural features of transgenic murine models of Alzheimer's disease. Neuropathol Appl Neurobiol. 2017;43(7): 553-570.
Crossref Google Scholar
4

Schroeder JP, Packard MG. Systemic or intra-amygdala injections of glucose facilitate memory consolidation for extinction of drug-induced conditioned reward. Eur J Neurosci. 2003;17(7): 1482-1488.
Crossref Google Scholar
5

Foster KA, Margraf RR, Turner DA. NADH hyperoxidation correlates with enhanced susceptibility of aged rats to hypoxia. Neurobiol Aging. 2008;29(4): 598-613.
Crossref Google Scholar
6

Yun J, Yeo IJ, Hwang CJ, et al. Estrogen deficiency exacerbates Aβ-induced memory impairment through enhancement of neuroinflammation, amyloidogenesis and NF-κB activation in ovariectomized mice. Brain Behav Immun. 2018;73: 282-293.
Crossref Google Scholar
7

Simpkins JW, Yang SH, Wen Y, Singh M. Estrogens, progestins, menopause and neurodegeneration: basic and clinical studies. Cell Mol Life Sci. 2005;62(3): 271-280.
Crossref Google Scholar
8

Xu Y, López M. Central regulation of energy metabolism by estrogens. Mol Metab. 2018;15: 104-115.
Crossref Google Scholar
9

Osterlund MK, Grandien K, Keller E, Hurd YL. The human brain has distinct regional expression patterns of estrogen receptor alpha mRNA isoforms derived from alternative promoters. J Neurochem. 2000;75(4): 1390-1397.
Crossref Google Scholar
10

Osterlund MK, Gustafsson JA, Keller E, Hurd YL. Estrogen receptor beta (ERbeta) messenger ribonucleic acid (mRNA) expression within the human forebrain: distinct distribution pattern to ERalpha mRNA. J Clin Endocrinol Metab. 2000;85(10): 3840-3846.
Crossref Google Scholar
11

Irwin RW, Yao J, To J, Hamilton RT, Cadenas E, Brinton RD. Selective oestrogen receptor modulators differentially potentiate brain mitochondrial function. J Neuroendocrinol. 2012;24(1): 236-248.
Crossref Google Scholar
12

Yager JD, Chen JQ. Mitochondrial estrogen receptors–new insights into specific functions. Trends Endocrinol Metabol. 2007;18(3): 89-91.
Crossref Google Scholar
13

Sarkar S, Jun S, Simpkins JW. Estrogen amelioration of Aβ-induced defects in mitochondria is mediated by mitochondrial signaling pathway involving ERβ, AKAP and Drp1. Brain Res. 2015;1616: 101-111.
Crossref Google Scholar
14

Winer JR, Maass A, Pressman P, et al. Associations between tau, β-amyloid, and cognition in Parkinson disease. JAMA Neurol. 2018;75(2): 227-235.
Crossref Google Scholar
15

Minoshima S, Giordani B, Berent S, Frey KA, Foster NL, Kuhl DE. Metabolic reduction in the posterior cingulate cortex in very early Alzheimer's disease. Ann Neurol. 1997;42(1): 85-94.
Crossref Google Scholar
16

Small GW, Mazziotta JC, Collins MT, et al. Apolipoprotein E type 4 allele and cerebral glucose metabolism in relatives at risk for familial Alzheimer disease. J Am Med Assoc. 1995;273(12): 942-947.
Crossref Google Scholar
17

Simpson IA, Carruthers A, Vannucci SJ. Supply and demand in cerebral energy metabolism: the role of nutrient transporters. J Cerebr Blood Flow Metabol. 2007;27(11): 1766-1791.
Crossref Google Scholar
18

Sonntag WE, Ramsey M, Carter CS. Growth hormone and insulin-like growth factor-1 (IGF-1) and their influence on cognitive aging. Ageing Res Rev. 2005;4(2): 195-212.
Crossref Google Scholar
19

Annenkov A. The insulin-like growth factor (IGF) receptor type 1 (IGF1R) as an essential component of the signalling network regulating neurogenesis. Mol Neurobiol. 2009;40(3): 195-215.
Crossref Google Scholar
20

Rojanathammanee L, Rakoczy S, Kopchick J, Brown-Borg HM. Effects of insulin-like growth factor 1 on glutathione S-transferases and thioredoxin in growth hormone receptor knockout mice. Age (Dordr). . 2014;36(4): 9687.
Crossref Google Scholar
21

Gazit N, Vertkin I, Shapira I, et al. IGF-1 receptor differentially regulates spontaneous and evoked transmission via mitochondria at hippocampal synapses. Neuron. 2016;89(3): 583-597.
Crossref Google Scholar
22

Deng W, Aimone JB, Gage FH. New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? Nat Rev Neurosci. 2010;11(5): 339-350.
Crossref Google Scholar
23

Mosconi L, Brys M, Switalski R, et al. Maternal family history of Alzheimer's disease predisposes to reduced brain glucose metabolism. Proc Natl Acad Sci U S A. 2007;104(48): 19067-19072.
Crossref Google Scholar
24

Brinton RD. The healthy cell bias of estrogen action: mitochondrial bioenergetics and neurological implications. Trends Neurosci. 2008;31(10): 529-537.
Crossref Google Scholar
25

Lane CA, Hardy J, Schott JM. Alzheimer's disease. Eur J Neurol. 2018;25(1): 59-70.
Crossref Google Scholar
26

Pike CJ. Sex and the development of Alzheimer's disease. J Neurosci Res. 2017;95(1–2): 671-680.
Crossref Google Scholar
27

Ryan J, Scali J, Carrière I, et al. Impact of a premature menopause on cognitive function in later life. BJOG. 2014;121(13): 1729-1739.
Crossref Google Scholar
28

Laws KR, Irvine K, Gale TM. Sex differences in cognitive impairment in Alzheimer's disease. World J Psychiatr. 2016;6(1): 54-65.
Crossref Google Scholar
29

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.
Crossref Google Scholar
30

Engler-Chiurazzi EB, Brown CM, Povroznik JM, Simpkins JW. Estrogens as neuroprotectants: estrogenic actions in the context of cognitive aging and brain injury. Prog Neurobiol. 2017;157: 188-211.
Crossref Google Scholar
31

Engler-Chiurazzi EB, Singh M, Simpkins JW. Reprint of: from the 90׳s to now: a brief historical perspective on more than two decades of estrogen neuroprotection. Brain Res. 2016;1645: 79-82.
Crossref Google Scholar
32

Wang JM, Hou X, Adeosun S, et al. A dominant negative ERβ splice variant determines the effectiveness of early or late estrogen therapy after ovariectomy in rats. PLoS One. 2012;7(3): e33493.
Crossref Google Scholar
33

López-Grueso R, Gambini J, Abdelaziz KM, et al. Early, but not late onset estrogen replacement therapy prevents oxidative stress and metabolic alterations caused by ovariectomy. Antioxidants Redox Signal. 2014;20(2): 236-246.
Crossref Google Scholar
34

Yao J, Irwin R, Chen S, Hamilton R, Cadenas E, Brinton RD. Ovarian hormone loss induces bioenergetic deficits and mitochondrial β-amyloid. Neurobiol Aging. 2012;33(8): 1507-1521.
Crossref Google Scholar
35

Lu Y, Sareddy GR, Wang J, et al. Neuron-Derived estrogen regulates synaptic plasticity and memory. J Neurosci. 2019;39(15): 2792-2809.
Crossref Google Scholar
36

Galluzzi L, Bravo-San Pedro JM, Kepp O, Kroemer G. Regulated cell death and adaptive stress responses. Cell Mol Life Sci. 2016;73(11–12): 2405-2410.
Crossref Google Scholar
37

Takasugi N, Tomita T, Hayashi I, et al. The role of presenilin cofactors in the gamma-secretase complex. Nature. 2003;422(6930): 438-441.
Crossref Google Scholar
38

Weksler ME, Szabo P, Relkin NR, Reidenberg MM, Weksler BB, Coppus AM. Alzheimer's disease and Down's syndrome: treating two paths to dementia. Autoimmun Rev. 2013;12(6): 670-673.
Crossref Google Scholar
39

Zhao Y, Bhattacharjee S, Jones BM, et al. Beta-amyloid precursor protein (βAPP) processing in Alzheimer's disease (AD) and age-related macular degeneration (AMD). Mol Neurobiol. 2015;52(1): 533-544.
Crossref Google Scholar
40

Yao Q, Feng M, Yang B, et al. Effects of ovarian hormone loss on neuritic plaques and autophagic flux in the brains of adult female APP/PS1 double-transgenic mice. Acta Biochim Biophys Sin (Shanghai). . 2018;50(5): 447-455.
Crossref Google Scholar
41

Yu W, Lu B. Synapses and dendritic spines as pathogenic targets in Alzheimer's disease. Neural Plast. 2012;2012: 247150.
Crossref Google Scholar
42

van Wijk N, Broersen LM, de Wilde MC, et al. Targeting synaptic dysfunction in Alzheimer's disease by administering a specific nutrient combination. J Alzheimers Dis. 2014;38(3): 459-479.
Crossref Google Scholar
43

Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Mol Med. 2016;8(6): 595-608.
Crossref Google Scholar
44

Mosconi L, Brys M, Switalski R, et al. Maternal family history of Alzheimer's disease predisposes to reduced brain glucose metabolism. Proc Natl Acad Sci U S A. 2007;104(48): 19067-19072.
Crossref Google Scholar
45

Brinton RD. The healthy cell bias of estrogen action: mitochondrial bioenergetics and neurological implications. Trends Neurosci. 2008;31(10): 529-537.
Crossref Google Scholar
46

Magistretti PJ. Neuron-glia metabolic coupling and plasticity. Exp Physiol. 2011;96(4): 407-410.
Crossref Google Scholar
47

Wallace DC. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet. 2005;39: 359-407.
Crossref Google Scholar
48

Li PA, Hou X, Hao S. Mitochondrial biogenesis in neurodegeneration. J Neurosci Res. 2017;95(10): 2025-2029.
Crossref Google Scholar
49

Mosconi L, Mistur R, Switalski R, et al. Declining brain glucose metabolism in normal individuals with a maternal history of Alzheimer disease. Neurology. 2009;72(6): 513-520.
Crossref Google Scholar
50

Shi Y, Yamada K, Liddelow SA, et al. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature. 2017;549(7673): 523-527.
Crossref Google Scholar
51

Wang Y, Mishra A, Brinton RD. Transitions in metabolic and immune systems from pre-menopause to post-menopause: implications for age-associated neurodegenerative diseases. F1000Res. 2020;9: F1000 Faculty Rev-68.
Crossref Google Scholar
52

Duelli R, Kuschinsky W. Brain glucose transporters: relationship to local energy demand. News Physiol Sci. 2001;16: 71-76.
Crossref Google Scholar
53

Ding F, Yao J, Zhao L, Mao Z, Chen S, Brinton RD. Ovariectomy induces a shift in fuel availability and metabolism in the hippocampus of the female transgenic model of familial Alzheimer's. PLoS One. 2013;8(3): e59825.
Crossref Google Scholar
54

Shi J, Simpkins JW. 17 beta-Estradiol modulation of glucose transporter 1 expression in blood-brain barrier. Am J Physiol. 1997;272(6 Pt 1): E1016-E1022.
Crossref Google Scholar
55

Long J, He P, Shen Y, Li R. New evidence of mitochondria dysfunction in the female Alzheimer's disease brain: deficiency of estrogen receptor-β. J Alzheimers Dis. 2012;30(3): 545-558.
Crossref Google Scholar
56

Santagati S, Melcangi RC, Celotti F, Martini L, Maggi A. Estrogen receptor is expressed in different types of glial cells in culture. J Neurochem. 1994;63(6): 2058-2064.
Crossref Google Scholar
57

Frater J, Lie D, Bartlett P, McGrath JJ. Insulin-like Growth Factor 1 (IGF-1) as a marker of cognitive decline in normal ageing: a review. Ageing Res Rev. 2018;42: 14-27.
Crossref Google Scholar
58

Hoshi M, Sato M, Kondo S, et al. Different localization of tau protein kinase I/glycogen synthase kinase-3 beta from glycogen synthase kinase-3 alpha in cerebellum mitochondria. J Biochem. 1995;118(4): 683-685.
Crossref Google Scholar
59

Bijur GN, Jope RS. Glycogen synthase kinase-3 beta is highly activated in nuclei and mitochondria. Neuroreport. 2003;14(18): 2415-2419.
Crossref Google Scholar
60

Yang K, Chen Z, Gao J, et al. The key roles of GSK-3β in regulating mitochondrial activity. Cell Physiol Biochem. 2017;44(4): 1445-1459.
Crossref Google Scholar
61

Hoeflich KP, Luo J, Rubie EA, Tsao MS, Jin O, Woodgett JR. Requirement for glycogen synthase kinase-3beta in cell survival and NF-kappaB activation. Nature. 2000;406(6791): 86-90.
Crossref Google Scholar
Genes & Diseases
Volume 9 Issue 5,
September 2022
Pages 1315-1331
DOI: 10.1016/j.gendis.2021.01.007
Cite this article:
Luo M, Zeng Q, Jiang K, et al. Estrogen deficiency exacerbates learning and memory deficits associated with glucose metabolism disorder in APP/PS1 double transgenic female mice. Genes & Diseases, 2022, 9(5): 1315-1331. https://doi.org/10.1016/j.gendis.2021.01.007

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Received: 28 October 2020
Revised: 15 January 2021
Accepted: 27 January 2021
Published: 16 February 2021
© 2022, Chongqing Medical University.

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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