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  • Print publication year: 2009
  • Online publication date: July 2010

Chapter 6 - The healthy cell bias of estrogen action through regulating glucose metabolism and mitochondrial function: implications for prevention of Alzheimer's disease

from Section 1 - Estrogens and cognition: perspectives and opportunities in the wake of the Women's Health Initiative Memory Study

Summary

Editors' introduction

Brinton provides a comprehensive review of the effects of estradiol on glycolytic enzymes and glucose metabolism in the brain and in neurons. Her analysis reveals a large body of corroborating evidence converging on the conclusion that estradiol promotes enhanced utilization of glucose in the brain, thereby helping neurons to meet the energy demands of neuronal activation. Seeing as how dysfunction of glucose metabolism and neuronal biogenetics are antecedents to Alzheimer's disease (AD), it is reasonable to speculate how the effects of estrogens on glucose metabolism might help stave off the disease. Her studies show, however, that as neurons become compromised such as in the context of aging and/or disease, the effects of estrogens can become deleterious and ultimately lead to the activation of apoptotic pathways and neuronal death. Hence the hypothesis that as neurons age and become increasingly stressed or compromised, the net effect of estrogens on oxidative metabolism and neuronal survival shifts from positive to negative. This healthy cell bias may explain some of the recent negative clinical results, and in particular how estrogenic therapy administered around the time of the perimenopause can be beneficial whereas the same therapy administered late in life and in the context of a developing pathology could be detrimental and result in significant cognitive decline.

References

1. Brinton RD. Investigative models for determining hormone therapy-induced outcomes in brain: evidence in support of a healthy cell bias of estrogen action. Ann N Y Acad Sci. 2005; 1052:57–74.
2. Morrison JH, Brinton RD, Schmidt PJ, Gore AC. Estrogen, menopause, and the aging brain: how basic neuroscience can inform hormone therapy in women. J Neurosci. 2006; 26(41):10332–48.
3. Wise PM. Estrogen therapy: does it help or hurt the adult and aging brain? Insights derived from animal models. Neuroscience. 2006;138(3):831–5.
4. Singh M, Sumien N, Kyser C, Simpkins JW. Estrogens and progesterone as neuroprotectants: what animal models teach us. Front Biosci. 2008;13:1083–9.
5. Nilsen J, Brinton RD. Impact of progestins on estrogen-induced neuroprotection: synergy by progesterone and 19-norprogesterone and antagonism by medroxyprogesterone acetate. Endocrinology. 2002;143(1):205–12.
6. 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(17):2123–9.
7. Resnick SM, Henderson VW. Hormone therapy and risk of Alzheimer disease: a critical time. JAMA. 2002;288(17):2170–2.
8. Yaffe K. Hormone therapy and the brain: deja vu all over again? JAMA. 2003;289(20):2717–19.
9. Sohrabji F. Estrogen: a neuroprotective or proinflammatory hormone? Emerging evidence from reproductive aging models. Ann N Y Acad Sci. 2005;1052:75–90.
10. Chen S, Nilsen J, Brinton RD. Dose and temporal pattern of estrogen exposure determines neuroprotective outcome in hippocampal neurons: therapeutic implications. Endocrinology. 2006;147(11):5303–13.
11. Sherwin BB, Henry JF. Brain aging modulates the neuroprotective effects of estrogen on selective aspects of cognition in women: a critical review. Front Neuroendocrinol. 2008;29(1):88–113.
12. Shumaker SA, Legault C, Kuller L, et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study. JAMA. 2004;291(24):2947–58.
13. Shumaker SA, Legault C, Rapp SR, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. JAMA. 2003;289(20):2651–62.
14. Sherwin BB. Estrogen and cognitive functioning in women. Endocr Rev. 2003;24(2):133–51.
15. Yaffe K, Sawaya G, Lieberburg I, Grady D. Estrogen therapy in postmenopausal women: effects on cognitive function and dementia. JAMA. 1998;279(9):688–95.
16. Petitti DB, Crooks VC, Chiu V, Buckwalter JG, Chui HC. Incidence of dementia in long-term hormone users. Am J Epidemiol. 2008;167(6):692–700.
17. Fillit H, Weinreb H, Cholst I, et al. Observations in a preliminary open trial of estradiol therapy for senile dementia-Alzheimer's type. Psychoneuroendocrinology. 1986;11(3):337–45.
18. Mulnard RA, Cotman CW, Kawas C, et al. Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial. Alzheimer's Disease Cooperative Study. JAMA. 2000;283(8):1007–15.
19. Henderson VW, Paganini-Hill A, Miller BL, et al. Estrogen for Alzheimer's disease in women: randomized, double-blind, placebo-controlled trial. Neurology. 2000;54(2):295–301.
20. Henderson VW, Hogan PE, Rapp SR, et al. Prior use of hormone therapy and incident Alzheimer's disease in the Women's Health Initiative Memory Study. Neurology. 2007;68(suppl.1):A205.
21. 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):E1016–22.
22. Cheng CM, Cohen M, Wang J, Bondy CA. Estrogen augments glucose transporter and IGF1 expression in primate cerebral cortex. FASEB J. 2001;15(6):907–15.
23. Bishop J, Simpkins JW. Estradiol enhances brain glucose uptake in ovariectomized rats. Brain Res Bull. 1995;36(3):315–20.
24. Nilsen J, Brinton RD. Mechanism of estrogen-mediated neuroprotection: regulation of mitochondrial calcium and Bcl-2 expression. Proc Natl Acad Sci USA. 2003;100(5):2842–7.
25. Nilsen J, Brinton RD. Mitochondria as therapeutic targets of estrogen action in the central nervous system. Curr Drug Targets CNS Neurol Disord. 2004;3(4):297–313.
26. Simpkins JW, Wang J, Wang X, et al. Mitochondria play a central role in estrogen-induced neuroprotection. Curr Drug Targets CNS Neurol Disord. 2005;4(1):69–83.
27. 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.
28. Simpkins JW, Dykens JA. Mitochondrial mechanisms of estrogen neuroprotection. Brain Res Rev. 2008;57(2):421–30.
29. Kostanyan A, Nazaryan K. Rat brain glycolysis regulation by estradiol-17 beta. Biochim Biophys Acta. 1992;1133(3):301–6.
30. Mannella P, Brinton RD. Estrogen receptor protein interaction with phosphatidylinositol 3-kinase leads to activation of phosphorylated Akt and extracellular signal-regulated kinase 1/2 in the same population of cortical neurons: a unified mechanism of estrogen action. J Neurosci. 2006;26(37):9439–47.
31. Gottlob K, Majewski N, Kennedy S, et al. Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase. Genes Dev. 2001;15(11):1406–18.
32. Miyamoto S, Murphy AN, Brown JH. Akt mediates mitochondrial protection in cardiomyocytes through phosphorylation of mitochondrial hexokinase-II. Cell Death Differ. 2008;15(3): 521–9.
33. Singh M. Ovarian hormones elicit phosphorylation of Akt and extracellular-signal regulated kinase in explants of the cerebral cortex. Endocrine Journal-UK. 2001;14(3):407–15.
34. Znamensky V, Akama KT, McEwen BS, Milner TA. Estrogen levels regulate the subcellular distribution of phosphorylated Akt in hippocampal CA1 dendrites. J Neurosci. 2003;23(6):2340–7.
35. Mendez P, Wandosell F, Garcia-Segura LM. Cross-talk between estrogen receptors and insulin-like growth factor-I receptor in the brain: cellular and molecular mechanisms. Front Neuroendocrinol. 2006;27(4):391–403.
36. Mendez P, Garcia-Segura LM. Phosphatidylinositol 3-kinase and glycogen synthase kinase 3 regulate estrogen receptor-mediated transcription in neuronal cells. Endocrinology. 2006;147(6):3027–39.
37. Cardona-Gomez GP, Mendez P, DonCarlos LL, Azcoitia I, Garcia-Segura LM. Interactions of estrogen and insulin-like growth factor-I in the brain: molecular mechanisms and functional implications. J Steroid Biochem Mol Biol. 2002;83(1/5):211–17.
38. Garcia-Segura LM, Cardona-Gomez GP, Chowen JA, Azcoitia I. Insulin-like growth factor-I receptors and estrogen receptors interact in the promotion of neuronal survival and neuroprotection. J Neurocytol. 2000;29(5/6):425–37.
39. Mendez P, Azcoitia I, Garcia-Segura LM. Estrogen receptor alpha forms estrogen-dependent multimolecular complexes with insulin-like growth factor receptor and phosphatidylinositol 3-kinase in the adult rat brain. Brain Res Mol Brain Res. 2003;112(1/2):170–6.
40. Carro E, Trejo JL, Gomez-Isla T, LeRoith D, Torres-Aleman I. Serum insulin-like growth factor I regulates brain amyloid-beta levels. Nat Med. 2002;8(12):1390–7.
41. Maki PM, Resnick SM. Longitudinal effects of estrogen replacement therapy on PET cerebral blood flow and cognition. Neurobiol Aging. 2000;21(2):373–83.
42. Rasgon NL, Silverman D, Siddarth P, et al. Estrogen use and brain metabolic change in postmenopausal women. Neurobiol Aging. 2005;26(2):229–35.
43. Liang WS, Reiman EM, Valla J, et al. Alzheimer's disease is associated with reduced expression of energy metabolism genes in posterior cingulate neurons. Proc Natl Acad Sci USA. 2008;105(11):4441–6.
44. Nilsen J, Brinton RD. Mechanism of estrogen-mediated neuroprotection: regulation of mitochondrial calcium and Bcl-2 expression. Proc Natl Acad Sci USA. 2003;100(5):2842–7.
45. Brinton RD, Chen S, Montoya M, et al. The Women's Health Initiative estrogen replacement therapy is neurotrophic and neuroprotective. Neurobiol Aging. 2000;21(3):475–96.
46. Nilsen J, Irwin RW, Gallaher TK, Brinton RD. Estradiol in vivo regulation of brain mitochondrial proteome. J Neurosci. 2007;27(51):14069–77.
47. Holmquist L, Stuchbury G, Berbaum K, et al. Lipoic acid as a novel treatment for Alzheimer's disease and related dementias. Pharmacol Ther. 2007;113(1):154–64.
48. Bettini E, Maggi A. Estrogen induction of cytochrome c oxidase subunit III in rat hippocampus. J Neurochem. 1992;58(5):1923–9.
49. Stirone C, Duckles SP, Krause DN, Procaccio V. Estrogen increases mitochondrial efficiency and reduces oxidative stress in cerebral blood vessels. Mol Pharmacol. 2005;68(4):959–65.
50. Lin M, Beal M. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature. 2006;443(7113):787–95.
51. Bubber P, Haroutunian V, Fisch G, Blass JP, Gibson GE. Mitochondrial abnormalities in Alzheimer brain: mechanistic implications. Ann Neurol. 2005;57(5):695–703.
52. Moreira PI, Santos MS, Seica R, Oliveira CR. Brain mitochondrial dysfunction as a link between Alzheimer's disease and diabetes. J Neurol Sci. 2007;257(1–2):206–14.
53. Cadenas E. Mitochondrial free radical production and cell signaling. Mol Aspects Med. 2004;25(1/2):17–26.
54. Yao J, Petanceska SS, Montine TJ, et al. Aging, gender and APOE isotype modulate metabolism of Alzheimer's A-beta peptides and F-isoprostanes in the absence of detectable amyloid deposits. J Neurochem. 2004;90(4):1011–18.
55. Borras C, Gambini J, Vina J. Mitochondrial oxidant generation is involved in determining why females live longer than males. Front Biosci. 2007;12:1008–13.
56. Vina J, Borras C, Gambini J, Sastre J, Pallardo FV. Why do females live longer than males? Importance of the upregulation of longevity-associated genes by oestrogenic compounds. FEBS Lett. 2005;579(12):2541–5.
57. Vina J, Sastre J, Pallardo FV, Gambini J, Borras C. Role of mitochondrial oxidative stress to explain the different longevity between genders: protective effect of estrogens. Free Radic Res. 2006;40(12):1359–65.
58. Duckles SP, Krause DN, Stirone C, Procaccio V. Estrogen and mitochondria: a new paradigm for vascular protection? Mol Interv. 2006;6(1):26–35.
59. Razmara A, Sunday L, Stirone C, et al. Mitochondrial effects of estrogen are mediated by ERα in brain endothelial cells. J Pharmacol Exp Ther. 2008;325(3):782–90.
60. Yang SH, Liu R, Perez EJ, et al. Mitochondrial localization of estrogen receptor beta. Proc Natl Acad Sci USA. 2004;101(12):4130–5.
61. Milner TA, Ayoola K, Drake CT, et al. Ultrastructural localization of estrogen receptor beta immunoreactivity in the rat hippocampal formation. J Comp Neurol. 2005;491(2):81–95.
62. Yager JD, Chen JQ. Mitochondrial estrogen receptors – new insights into specific functions. Trends Endocrinol Metab. 2007;18(3):89–91.
63. McEwen B, Akama K, Alves S, et al. Tracking the estrogen receptor in neurons: implications for estrogen-induced synapse formation. Proc Natl Acad Sci USA. 2001;98(13):7093–100.
64. Levin ER. Cell localization, physiology, and nongenomic actions of estrogen receptors. J Appl Physiol. 2001;91(4):1860–7.
65. Wu TW, Brinton RD. Estrogen membrane receptor imaging coupled with estradiol activation of intracellular calcium rise and ERK activation in single neurons. Society for Neuroscience Abstracts; 2004.
66. Zhao L, Chen S, Ming Wang J, Brinton RD. 17beta-estradiol induces Ca2+ influx, dendritic and nuclear Ca2+ rise and subsequent cyclic AMP response element-binding protein activation in hippocampal neurons: a potential initiation mechanism for estrogen neurotrophism. Neuroscience. 2005;132(2):299–311.
67. Wagner BK, Kitami T, Gilbert TJ, et al. Large-scale chemical dissection of mitochondrial function. Nat Biotechnol. 2008;26(3):343–51.
68. Milner TA, Lubbers LS, Alves SE, McEwen BS. Nuclear and extranuclear estrogen binding sites in the rat forebrain and autonomic medullary areas. Endocrinology. 2008;149(7):3306–12.
69. Milner TA, McEwen BS, Hayashi S, et al. Ultrastructural evidence that hippocampal alpha estrogen receptors are located at extranuclear sites. J Comp Neurol. 2001;429(3):355–71.
70. 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.
71. Murphy AN, Fiskum G, Beal MF. Mitochondria in neurodegeneration: bioenergetic function in cell life and death. J Cereb Blood Flow Metab. 1999;19(3):231–45.
72. Mattson MP. Pathways towards and away from Alzheimer's disease. Nature. 2004;430(7000):631–9.
73. Melov S. Modeling mitochondrial function in aging neurons. Trends Neurosci. 2004;27(10):601–6.
74. Martins IJ, Hone E, Foster JK, et al. Apolipoprotein E, cholesterol metabolism, diabetes, and the convergence of risk factors for Alzheimer's disease and cardiovascular disease. Mol Psychiatry. 2006;11(8):721–36.
75. Mosconi L, Sorbi S, de Leon MJ, et al. Hypometabolism exceeds atrophy in presymptomatic early-onset familial Alzheimer's disease. J Nucl Med. 2006;47(11):1778–86.
76. Reiman EM, Chen K, Caselli RJ, et al. Cholesterol-related genetic risk scores are associated with hypometabolism in Alzheimer's-affected brain regions. Neuroimage. 2008;40(3):1214–21.
77. Mosconi L, Tsui WH, Herholz K, et al. Multicenter standardized 18F-FDG PET diagnosis of mild cognitive impairment, Alzheimer's disease, and other dementias. J Nucl Med. 2008;49(3):390–8.
78. Blalock EM, Chen KC, Sharrow K et al. Gene microarrays in hippocampal aging: statistical profiling identifies novel processes correlated with cognitive impairment. J Neurosci. 2003;23(9):3807–19.
79. Blalock EM, Geddes JW, Chen KC, et al. Incipient Alzheimer's disease: microarray correlation analyses reveal major transcriptional and tumor suppressor responses. Proc Natl Acad Sci USA. 2004;101(7):2173–8.
80. Reiman EM, Chen K, Alexander GE, et al. Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia. Proc Natl Acad Sci USA. 2004;101(1):284–9.
81. Rowe WB, Blalock EM, Chen KC, et al. Hippocampal expression analyses reveal selective association of immediate-early, neuroenergetic, and myelinogenic pathways with cognitive impairment in aged rats. J Neurosci. 2007;27(12):3098–110.
82. Miller JA, Oldham MC, Geschwind DH. A systems level analysis of transcriptional changes in Alzheimer's disease and normal aging. J Neurosci. 2008;28(6):1410–20.
83. Alexander GE, Chen K, Pietrini P, Rapoport SI, Reiman EM. Longitudinal PET evaluation of cerebral metabolic decline in dementia: a potential outcome measure in Alzheimer's disease treatment studies. Am J Psychiatry. 2002;159(5):738–45.
84. Craft S. Insulin resistance and Alzheimer's disease pathogenesis: potential mechanisms and implications for treatment. Curr Alzheimer Res. 2007;4(2):147–52.
85. Ishii K, Kitagaki H, Kono M, Mori E. Decreased medial temporal oxygen metabolism in Alzheimer's disease shown by PET. J Nucl Med. 1996;37(7):1159–65.
86. Magistretti PJ, Pellerin L. Cellular bases of brain energy metabolism and their relevance to functional brain imaging: evidence for a prominent role of astrocytes. Cereb Cortex. 1996;6(1):50–61.
87. Randle PJ. Regulatory interactions between lipids and carbohydrates: the glucose fatty acid cycle after 35 years. Diabetes Metab Rev. 1998;14(4):263–83.
88. Ishii K, Minoshima S. PET is better than perfusion SPECT for early diagnosis of Alzheimer's disease. Eur J Nucl Med Mol Imaging. 2005;32(12):1463–5.
89. Blass J, Sheu R, Gibson G. Inherent abnormalities in energy metabolism in Alzheimer disease. Interaction with cerebrovascular compromise. Ann N Y Acad Sci. 2000;903:204–21.
90. Hoyer S, Nitsch R, Oesterreich K. Predominant abnormality in cerebral glucose utilization in late-onset dementia of the Alzheimer type: a cross-sectional comparison against advanced late-onset and incipient early-onset cases. J Neural Transm Park Dis Dement Sect. 1991;3(1):1–14.
91. Toescu EC, Verkhratsky A, Landfield PW. Ca2+ regulation and gene expression in normal brain aging. Trends Neurosci. 2004;27(10):614–20.
92. Asthana S, Brinton RD, Henderson VW, et al. Frontiers Proposal. National Institute on Aging. Bench to Bedside: Estrogen as a Case Study. AGE. 2009; in press.