Skip to main content
Springer Nature Link
Log in

Cellular and molecular basis of estrogen’s neuroprotection

Potential relevance for Alzheimer’s disease

  • Original Articles
  • Published:
Save article
View saved research
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Alzheimer’s disease (AD) is one of the most common types of dementia among the aged population, with a higher prevalence in women. The reason for this latter observation remained unsolved for years, but recent studies have provided evidence that a lack of circulating estrogen in postmenopausal women could be a relevant factor.

Moreover, follow-up studies among postmenopausal women who had received estrogenreplacement therapy (ERT), suggested that they had a markedly reduced risk of developing AD. In addition, studies among older women who already had AD indeed confirmed that a decrease in estrogen levels was likely to be an important factor in triggering the pathogenesis of the disease.

In this review article, we will discuss the evidence suggesting that estrogen may have a protective role against AD, mainly through its action as: a trophic factor for cholinergic neurons, a modulator for the expression of apolipoprotein E (ApoE) in the brain, an antioxidant compound decreasing the neuronal damage caused by oxidative stress, and a promoter of the physiological nonamyloidogenic processing of the amyloid precursor protein (APP), decreasing the production of the amyloid-Β-peptide (AΒ), a key factor in the pathogenesis of AD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+
from $39.99 /Month
  • Starting from 10 chapters or articles per month
  • Access and download chapters and articles from more than 300k books and 2,500 journals
  • Cancel anytime
View plans

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Explore related subjects

Discover the latest articles, books and news in related subjects, suggested using machine learning.

References

  • Alvarez J., Moreno R. D., and Inestrosa N. C. (1995) Mitosis of Schwan cells and demyelination are induced by the amyloid precursor protein and other protease inhibitors in the rat sciatic nerve.Eur. J. Neurosci. 7, 152–159.

    PubMed  CAS  Google Scholar 

  • Bachman D. K., Wolf P. A., and Linn R. (1992) Prevalence of dementia and probable senile dementia of the Alzheimer type in the Framingham study.Neurology 42, 115–119.

    PubMed  CAS  Google Scholar 

  • Banker G. A. (1980) Trophic interactions between astroglial cells and hippocampal neurons in culture.Science 209, 809–810.

    PubMed  CAS  Google Scholar 

  • Behl C., Davis J., Lesley R., and Schunbert D. (1994) Hydrogen peroxide mediates amyloid-beta protein toxicity.Cell 77, 817–827.

    PubMed  CAS  Google Scholar 

  • Behl C., Davis J., Cole G. M., and Schubert D. (1992) Vitamin E protects nerve cells from amyloid-beta protein toxicity.Biochem. Biophys. Res. Commun. 186, 944–990.

    PubMed  CAS  Google Scholar 

  • Behl C., Thomas S., Lezoulac’h F., Post A., Widmann M., Newton C. J., and Holsboer F. (1997) Neuroprotection against oxidative stress by estrogen: structure-activity relationship.Mol. Pharmacol. 51, 535–541.

    PubMed  CAS  Google Scholar 

  • Behl C. W., Widman M. T., and Holsboer F. (1995) 17-beta-estradiol protects neurons from oxidative stress-induced cell death in vitro.Biochem. Biophys. Res. Commun. 216, 473–478.

    PubMed  CAS  Google Scholar 

  • Bellosta S., Nathan B. P., Orth M., Dong L. M., Mahley R. W., and Pitas R. E. (1995) Stable expression and secretion of apolipoproteins E3 and E4 in mouse neuroblastoma cells produces differential effects on neurite outgrowth.J. Biol. Chem. 270, 27,063–27,071.

    CAS  Google Scholar 

  • Bertrand P., Poirier J., Tomiichiro O., Finch C. E., and Pasinetti G. M. (1995) Association of apolipoprotein E genotype with brain levels of apolipoprotein E and apolipoprotein J (clustering) in Alzheimer disease.Mol. Brain Res. 33, 174–178.

    PubMed  CAS  Google Scholar 

  • Birge S. J. (1996) Is there a role of estrogen replacement therapy in the prevention and treatment of dementia?J. Amer. Geriat. Soc. 44, 865–870.

    PubMed  CAS  Google Scholar 

  • Blass J. P. and Poirier J. (1996) Pathology of the Alzheimer syndrome, inClinical Diagnosis and Management of Alzheimer’s Disease, (Gauthier S., ed.) Martin Dunitz Press, London, pp. 17–31.

    Google Scholar 

  • Boyles J. K., Zoellner C. D., Anderson L. J., Kosick L. M., Pitas R. E., Hui D. Y., Mahley R. W., Gebicke-Haerter P. J., Ignatius M. J., and Shooter E. M. (1989) A role for apolipoprotein E, apolipoprotein A-1, and low density lipoprotein receptors in cholesterol transport during regeneration and remyelinization of the rat sciatic nerve.J. Clin. Invest. 83, 1015–1031.

    PubMed  CAS  Google Scholar 

  • Braughler J. M. and Pregenzer J. F. (1989) The 21-aminosteroid inhibitors of lipid peroxidation: reactions with lipid peroxyl and phenoxy radicals.Free Rad. Biol. Med. 7, 125–130.

    PubMed  CAS  Google Scholar 

  • Breedlove S. M. (1992) Sexual dimorphism in the vertebrate nervous system.J. Neurosci. 12, 4133–4142.

    PubMed  CAS  Google Scholar 

  • Breen K., Bruce M., and Anderton B. H. (1991) Betaamyloid precursor protein mediates neuronal cell-cell and cell-surface adhesion.J. Neurosci. Res. 28, 90–100.

    PubMed  CAS  Google Scholar 

  • Bronfman F. C., Soto C., Tapia L., Tapia V., and Inestrosa N. C. (1996) Extracellular matrix regulates the amount of the beta-amyloid precursor protein and its amyloidogenic fragments.J. Cell. Physiol. 166, 360–369.

    PubMed  CAS  Google Scholar 

  • Brown R. H. (1995) Amyotrophic lateral sclerosis: recent insights from genetics and transgenic mice.Cell 80, 687–695.

    PubMed  CAS  Google Scholar 

  • Bu G., Maksymovitch E. A., Nerbonne J. M., and Schwartz A. L. (1994) Expression and function of the low density lipoprotein receptor-related protein (LRP) in mammalian central neurons.J. Biol. Chem. 269, 18,521–18,528.

    CAS  Google Scholar 

  • Carpenter M. K., Hassinger T. D., Whalen L. R., and Kater S. B. (1994) CNS white matter can be altered to support neuronal outgrowth.J. Neurosci. Res. 37, 1–14.

    PubMed  CAS  Google Scholar 

  • Chen M. and Yankner B. A. (1991) An antibody to beta-amyloid and the amyloid precursor inhibits cell-substratum adhesion in many mammalian cell types.Neurosci. Lett. 125, 223–226.

    PubMed  CAS  Google Scholar 

  • Christie R. H., Chung H., Rebeck G. W., Strickland D., and Hyman B. (1996) Expression of the very low-density lipoprotein receptor (VLDL-r), an apolipoprotein-E receptor, in the central nervous system and in Alzheimer’s disease.J. Neuropathol. Exp. Neurol. 55, 491–498.

    PubMed  CAS  Google Scholar 

  • Copain A., Koh J. Y., and Cotman C. W. (1991) Betaamyloid increases neuronal susceptibility to injury by glucose deprivation.NeuroReport 2, 763–765.

    Google Scholar 

  • Corder E. H., Saunders A. M., Strittmatter W. J., Schmechel D. E., Gaskell P. C., Small G. W., Roses A. D., Haines J. L., and Pericak-Vance M. A. (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families.Science. 261, 921–923.

    PubMed  CAS  Google Scholar 

  • Corder E. H., Saunders A. M., Strittmatter W. J., Schmechel D. E., Gaskell P. C., Jr., Rimmler J. B., Locke P. A., Conneally P. M., Schmader K. E., and Tanzi R. E. (1995) Apolipoprotein E, survival in Alzheimer’s disease patients, and the competing risks of death and Alzheimer’s disease.Neurology 45, 1323–1328.

    PubMed  CAS  Google Scholar 

  • Coyle J. T. and Puttfarken P. (1993) Oxidative stress, glutamate and neurodegenerative disorders.Science 262, 689–695.

    PubMed  CAS  Google Scholar 

  • Das S. K., Taylor J. A., Korach K. S., Paria B. C., Dey S. K., and Lubahn D. B. (1997) Estrogenic responses in estrogen-α deficient mice reveal a distinct estrogen signaling pathway.Proc. Natl. Acad. Sci. USA 94, 12,786–12,791.

    CAS  Google Scholar 

  • Dickson R. B., Mc Manaway M. E., and Lippman M. E. (1986) Estrogen-induced factors of breast cancer cells partially replace estrogen to promote tumor growth.Science 232, 1540–1543.

    PubMed  CAS  Google Scholar 

  • Drouva S. V., Gorenne I., Laplante E., Rerat E., Enjalbert A., and Kordon C. (1990) Estradiol modulates protein kinase C activity in the rat pituitary in vivo and in vitro.Endocrinology 126, 536–544.

    PubMed  CAS  Google Scholar 

  • Elkabes S., DiCicco-Bloom E. M., and Black I. B. (1996) Brain microglia/macrophages express neurotrophins that selectively regulate microglial proliferation and function.J. Neurosci. 16, 2508–2521.

    PubMed  CAS  Google Scholar 

  • Elshourbagy N. A., Liao W. S., Mahley R. W., and Taylor J. M. (1985) Apolipoprotein E mRNA is abundant in the brain and adrenals, as well as in the liver, and is present in other peripheral tissues of rats and marmosets.Proc. Natl Acad. Sci. USA 82, 203–207.

    PubMed  CAS  Google Scholar 

  • Evans R. M. (1988) The steroid and thyroid receptor superfamily.Science 240, 889–895.

    PubMed  CAS  Google Scholar 

  • Fillit H., Weinreb H., Cholst I., Luine V., Mc Ewen B., Amador R., and Zabriskie J. (1986). Observation in a preliminary open trial of estradiol therapy for senile dementia: Alzheimer’s type.Psychoneuroendocrinology 11, 337–345.

    PubMed  CAS  Google Scholar 

  • Fisher W., Gage F., and Bjorklund A. (1989) Degenerative changes in forebrain cholinergic nuclei correlate with cognitive impairments in aged rats.Eur. J. Neurosci. 1, 34–35.

    Google Scholar 

  • Garcia-Segura L. M., Chowen J. A., Párducz, A., and Naftolin F. (1994) Gonadal hormones as promoters of structural synaptic plasticity: cellular mechanisms.Prog. Neurobiol. 44, 279–307.

    PubMed  CAS  Google Scholar 

  • Gibbs R. B. (1994) Estrogen and nerve growth factor related systems in brain.Ann. NY Acad. Sci. 743, 165–199.

    PubMed  CAS  Google Scholar 

  • Gibbs R. B. (1997) Effects of estrogen on basal forebrain cholinergic neurons vary as a function of dose and duration of treatment.Brain Res. 757, 10–16.

    PubMed  CAS  Google Scholar 

  • Haass C. and Selkoe D. J. (1993) Cellular processing of beta-amyloid precursor protein and the genesis of amyloid-beta-peptide.Cell 75, 1039–1042.

    PubMed  CAS  Google Scholar 

  • Hall E. D., Pazara K. E., and Linseman K. L. Sex differences in postischemic neuronal necrosis in gerbils.J. Cereb. Blood Flow Metab. 11, 292–298.

  • Henderson V., Paganini-Hill A. A., Emanuel C. K., Dunn M. E., and Buckwelker J. G. (1994) Estrogen replacement therapy in older women: comparison between Alzheimer’s disease cases and nondemented controls.Arch. Neurol. 51, 896–899.

    PubMed  CAS  Google Scholar 

  • Honjo H., Ogino Y., Naitoh K., Urabe M., Kitawaki J., Yasuda J., Yamamoto T., Ishihara S., Okada H., Yonezawa T., Hayashi K., and Nambara T. (1989) In vivo effects by estrone sulfate on the central nervous system: senile dementia (Alzheimer’s type).J. Steroid Biochem. 34, 521–525.

    PubMed  CAS  Google Scholar 

  • Honjo J., Tamura T., Matsumoto Y., Kawata M., Ogino Y., Tamaka K., Yamamoto T., Ueda S., and Okado H. (1992) Estrogen as a growth factor to central nervous cells.J. Steroid. Biochem. 41, 633–635.

    CAS  Google Scholar 

  • Ishiguro M., Imai Y., and Kohsaka S. (1995) Expression and distribution of low density lipoprotein receptor-related protein mRNA in the rat central nervous system.Brain Res. Mol. Brain Res. 33, 37–46.

    PubMed  CAS  Google Scholar 

  • Jaffe A. B., Torand-Allerand C. D., Greengard P., and Gandy S. E. (1994) Estrogen regulates metabolism of Alzheimer amyloid beta precursor protein.J. Biol. Chem. 269, 13,065–13,068.

    CAS  Google Scholar 

  • Jing S., Tapley P., and Barbacid M. (1992) Nerve growth factor mediates signal transduction through trk homodimer receptors.Neuron 9, 1067–1079.

    PubMed  CAS  Google Scholar 

  • Jones K. J. (1988) Steroid hormones and neurotrophism: relationship to nerve injury.Metab. Brain. Dis. 3, 1–18.

    PubMed  CAS  Google Scholar 

  • Kaplan D. R., Martin-Zanca D., and Parada L. F. (1991a) Tyrosine phosphorylation and tyrosine kinase activity of the trk-proto-oncogene produced by NGF.Nature 350, 158–160.

    PubMed  CAS  Google Scholar 

  • Kaplan D. R., Hempstead B., Martin-Zanca D., Chao M. V., and Parada L. F. (1991b) The trk proto-oncogene product: a signal transducing receptor for nerve growth factor.Science 252, 554–558.

    PubMed  CAS  Google Scholar 

  • Kibbey M. C., Jucker M., Weeks B. S., Neve R. L., Van Norstrand W. E., and Kleinman H. K. (1993) Beta-amyloid precursor protein binds to neuritepromoting IKVAV site of Laminin.Proc. Natl. Acad. Sci. USA 90, 10,150–10,153.

    CAS  Google Scholar 

  • Kim D. H., Iijima H., Goto K., Sakai J., Ishii H., Kim H. J., Suzuki H., Kondo H., Saeki S., and Yamamoto T. (1996) Human apolipoprotein E receptor 2. A novel lipoprotein receptor of the low density lipoprotein receptor family predominantly expressed in brain.J. Biol. Chem. 271, 8373–80.

    PubMed  CAS  Google Scholar 

  • Koh J. Y., Yang L. L., and Cotman C. W. (1990) Betaamyloid protein increases the vulnerability of culture cortical neurons to excitotoxic damage.Brain. Res. 533, 315–320.

    PubMed  CAS  Google Scholar 

  • Korach K. S. (1994) Insights from the study of animals lacking functional estrogen receptor.Science 266, 1524–1527.

    PubMed  CAS  Google Scholar 

  • Kuiper G. G., Enmark E., Pelto-Huikko M., Nilsson S., and Gustafsson J. A. (1996) Cloning of a novel estrogen receptor expressed in rat prostate and ovary.Proc. Natl. Acad. Sci. USA 93, 5925–5930.

    PubMed  CAS  Google Scholar 

  • Kushwaha R. S., Foster D. M., Barrett K. D., Carey K. D., and Bernard M.G. (1991) Metabolic regulation of plasma apolipoprotein E by estrogen and progesterone in the baboon (Papio sp.).Metabolism 40, 93–100.

    PubMed  CAS  Google Scholar 

  • Landers J. P. and Spelsberg T. C. (1992) New concepts in steroid hormone action: transcription factors, proto-oncogenes, and the cascade model for steroid regulation of gene expression.Crit. Rev. Eukaryotic Gene Expression 2, 19–63.

    CAS  Google Scholar 

  • Lobo R. A. (1995) Benefits and risks of estrogen replacement therapy.Arn. J. Obstet. Gynecol. 173, 982–989.

    CAS  Google Scholar 

  • Lockhart B. P., Benicourt C., Junien J.-L., and Privat A. (1994) Inhibition of free radical formation fail to alternate direct beta-amyloid peptide-mediated neurotoxicity in rat hippocampal cultures.J. Neurosci. Res. 39, 494–505.

    PubMed  CAS  Google Scholar 

  • Lubahn D. B., Moyer J. S., Golding T. S., Course J. F., Korach K. S., and Smities O. (1993) Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene.Proc. Natl. Acad. Sci. USA 90, 11162–11166.

    PubMed  CAS  Google Scholar 

  • Luine V. N. (1992) Estradiol increases choline acetyl transferase activity in specific basal forebrain nuclei and projection area of female rats.Exp. Neurol. 89, 484–490.

    Google Scholar 

  • Lustig R. H. (1994) Anin vitro model for the effects of estrogen on neurons employing estrogen receptor-transfected PC12 cells.J. Neurosci. 14, 3945–3957.

    PubMed  CAS  Google Scholar 

  • Mahley R. W. (1989) Apolipoprotein E: cholesterol transport protein with expanding role in cell biology.Science 240, 622–630.

    Google Scholar 

  • Mahley R. W. (1996) Heparan sulfate proteoglycan/low density lipoprotein receptor-related protein pathway involved in type III hyperlipoproteinemia and Alzheimer’s disease.Isr. J. Med. Sci. 32, 414–29.

    PubMed  CAS  Google Scholar 

  • Maizels E. T., Miller J. B., Cutler R. J., Jackiw V., Carney E. M., Mizuno K., Ohno S., and Hunzicker D. M. (1992) Estrogen modulates Ca2[female]-independent lipid-stimulated kinase in the rabbit corpus luteum of pseudopregnancy. Identification of luteal estrogen-modulated lipid-stimulated kinase as protein kinase C delta.J. Biol Chem. 267, 17,061–17,068.

    CAS  Google Scholar 

  • Masliah E., Mallory M., Ge N., Alford M., Veinbergs I., and Rose A. D. (1995) Neurodegeneration in the central nervous system of apoE-deficient mice.Exp. Neurol. 136, 107–122.

    PubMed  CAS  Google Scholar 

  • Mattson M. P., Cheng B., Davis D., Bryant K., Lieberburg I., and Rydel R. E. (1992) Beta-amyloid peptide destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity.J. Neurosci. 12, 376–389.

    PubMed  CAS  Google Scholar 

  • Mc Ewen B. S. (1981) Endocrine effects on the brain and their relationship to behavior, inBasic Neurochemistry, 3rd ed. Little Crown & Co., Boston pp. 775–799.

    Google Scholar 

  • Mc Ewen B. S. (1988) Steroid hormones in the brain: linking nature and nurture.Neurochem. Res. 13, 663–669.

    CAS  Google Scholar 

  • Mc Ewen B. S., Coirini H., Danielsson A., Frankfurt M., Gould E., Mendelson S., Segarra A., and Wooley C. (1991) Steroid and thyroid hormones modulate a changing brain.J. Steroid Biochem. Mol Biol. 40, 1–14.

    CAS  Google Scholar 

  • Mc Ewen B. S., de Kloet E. R., and Rostene W. (1986) Adrenal steroid receptors and actions in the nervous system.Physiol. Rev. 66, 1121–1188.

    CAS  Google Scholar 

  • Mc Ewen B. S., Gerlach J. L., and Micco D. J. (1975) Putative glucocorticoid receptors in hippocampus and other regions of the rat brain, inThe Hippocampus: A Comprehensive Treatise. (Issacson, R. and Pribramm, K., eds.) Plenum, New York, pp. 285–322.

    Google Scholar 

  • Mc Ewen B. S., Zigmond R. E., and Gerlach J. (1972) Sites of steroid binding and action in the brain, inStructure and Function of Nervous Tissue, vol. 5. (G.H. Bourne, ed.) Academic, New York. pp. 205–291.

    Google Scholar 

  • Mecocci P. L., MacGarvey U., and Beal M. F. (1994) Oxidative damage to mitochondrial DNA is increased in Alzheimer’s disease.Ann. Neurol. 36, 747–750.

    PubMed  CAS  Google Scholar 

  • Miranda R. C. and Toran-Allerand C. D. (1992) Developmental expression of estrogen receptor mRNA in the rat cerebral cortex: a nonisotopic in situ hybridization histochemistry study.Cereb. Cortex 2, 1–15.

    PubMed  CAS  Google Scholar 

  • Miranda R., Sohrabji F., Singh M., and Toran-Allerand C. D. (1996) Nerve growth factor (NGF) regulation of estrogen receptors in expiant cultures of the developing forebrain.J. Neurobiol. 31, 77–87.

    PubMed  CAS  Google Scholar 

  • Milward E. A., Papadopoulos R., Fuller S. J., Moir R. D., Small D., Beyreuther K., and Masters C. L. (1992) The amyloid precursor protein of AD is a mediator of the effects of nerve growth factor on neurite outgrowth.Neuron 9, 129–137.

    PubMed  CAS  Google Scholar 

  • Milward E. A., Papadopoulos R., Fuller S. J., Moir R. D., Small D., Beyreuther K., and Masters C. L. (1992) The amyloid precursor protein of AD is a mediator of the effects of nerve growth factor on neurite outgrowth.Neuron 9, 129–137.

    PubMed  CAS  Google Scholar 

  • Mosselman S., Polman J., Djikema R. (1996) ERΒ: identification and characterization of a novel human estrogen receptor.FEBS Lett. 392, 49–53.

    PubMed  CAS  Google Scholar 

  • Mukai K., Daifuku K., and Yokoyama S. (1990) Stopped-flow investigation of antioxidant activity of estrogen in solution.Biochem. Biophys. Acta. 1035, 348–352.

    PubMed  CAS  Google Scholar 

  • Nakai M., Kawamata T., Taniguchi T., Maeda K., and Tanaka C. (1996) Expression of apolipoprotein E mRNA in rat microglia.Neurosci. Lett. 211, 41–44.

    PubMed  CAS  Google Scholar 

  • Namba Y., Tomonaga M., Kawasaki H., Otomo E., and Ikeda L. (1991) Apolipoprotein E immunoreactivity in cerebral amyloid deposits and neurofibrillary tangles in Alzheimer’s disease and kuru plaque amyloid in Creutzfeldt-Jacob disease.Brain. Res. 541, 163–166.

    PubMed  CAS  Google Scholar 

  • Narita M., Bu G., Holtzman D. M., and Schwartz A. L. (1997) The low-density lipoprotein receptorrelated protein, a multifunctional apolipoprotein E receptor, modulates hippocampal neurite development.J. Neurochem. 68, 587–595.

    PubMed  CAS  Google Scholar 

  • Nathan B. P., Bellosta S., Sanan D. A., Weisgraber K. H., Mahley R. W., and Pitas R. E. (1994) Differential effects of apolipoproteins E3 and E4 on neuronal growth in vitro.Science 264, 850–852.

    PubMed  CAS  Google Scholar 

  • Newton C. J., Trapp T., and Pagotto U. (1994) The estrogen receptor modulates growth of pituitary tumor cells in the absence of exogenous estrogen.J. Mol. Endocrinol. 12, 303–312.

    PubMed  CAS  Google Scholar 

  • Pace P., Taylor J., Suntharalingam S., Coombes R. C., and Ali S. (1997) Human estrogen receptor Β binds DNA in a manner similar to and dimerizes with estrogen receptor α.J. Biol. Chem. 272, 25,832–25,838.

    CAS  Google Scholar 

  • Paganini-Hill A. and Henderson V. W. (1994) Estrogen deficiency increases the risk of Alzheimer’s disease in women.Am. J. Epidemol. 140, 256–261.

    CAS  Google Scholar 

  • Paganini-Hill A. and Henderson V. W. (1996) Estrogen replacement therapy and risk of Alzheimer disease.Arch. Intern. Med. 156, 2213–2217.

    PubMed  CAS  Google Scholar 

  • Parthasarathy S. S., Steinberg D., and Witztum J. L. (1992) The role of oxidized low-density lipoproteins in the pathogenesis of atherosclerosis.Ann. Rev. Med. 43, 219–225.

    PubMed  CAS  Google Scholar 

  • Pitas R. E., Boyles J. K., Lee S. H., Foss D., and Mahley R. W. (1987) Lipoproteins and their receptors in the central nervous system-characterization of the lipoproteins in cerebrospinal fluid and identification of apolipoprotein B,E (LDL) receptors in the brain.J. Biol. Chem. 262, 14,352–14,360.

    CAS  Google Scholar 

  • Pitas R. E., Boyles J. K., Lee S. H., Foss D., and Mahley R. W. (1987) Astrocytes synthesize apolipoprotein E and metabolize apolipoprotein Econtaining lipoproteins.Biochim. Biophys. Acta 917, 148–161.

    PubMed  CAS  Google Scholar 

  • Poirier J. (1994) Apolipoprotein E in animal models of CNS injury and in Alzheimer’s disease.Trends Neurosci. 17, 525–530.

    PubMed  CAS  Google Scholar 

  • Poirier J., Baccichet A., Dea D., and Gauthier S. (1993) Cholesterol synthesis and lipoprotein reuptake during synaptic remodeling in hippocampus in adult rats.Neuroscience 55, 81–90.

    PubMed  CAS  Google Scholar 

  • Poirier J., Davignon J., Bouthillier D., Kogan S., Bertrand P., and Gauthier S. (1993) Apolipoprotein E polymorphism and Alzheimer’s disease.Lancet 342, 697–699.

    PubMed  CAS  Google Scholar 

  • Poirier J., Hess M., May P. C., and Finch C. E. (1991) Astrocytic apolipoprotein E mRNA and GPAP mRNA in hippocampus after etorhinal cortex lesioning.Mol. Brain Res. 11, 97–106.

    PubMed  CAS  Google Scholar 

  • Puttfarcken P. S., Manelli A. M., Falduto M. T., Getz G. S., and LaDu M. J. (1997) Effect of apolipoprotein E on neurite outgrowth and Β-amyloid-induced toxicity in developing rat primary hippocampal cultures.J. Neurochem. 68, 760–769.

    PubMed  CAS  Google Scholar 

  • Rebeck G. W., Reiter J. S., Strickland D. K., and Hyman B. T. (1993) Apolipoprotein E in sporadic Alzheimer’s disease: allelic variation and receptor interactions.Neuron 11, 575–580.

    PubMed  CAS  Google Scholar 

  • Rifici V. and Khachadurian A. K. (1992) The inhibition of low-density lipoprotein oxidation by 17-beta estradiol.Metabolism 41, 1110–1114.

    PubMed  CAS  Google Scholar 

  • Sacks F. M. and Walsh B. W. (1994) Sex hormones and lipoprotein metabolism.Curt. Opin. Lipidol. 5, 236–240.

    CAS  Google Scholar 

  • Saitoh T., Sundsmo M., Rock J.-M., Kimura N., Cole G., Schubert D., Oltersdorf D., and Schenk D. B. (1989) Secreted form of amyloid-beta protein precursor is involved in the growth regulation of fibroblasts.Cell 58, 615–622.

    PubMed  CAS  Google Scholar 

  • Schmechel D. E., Saunders A. M., Strittmatter W. J., Crain B. J., Hulette C. M., Joo S. H., Pericak-Vance M. A., Goldgaber D., and Roses A. D. (1993) Increased amyloid Β-peptide deposition in cerebral cortex as a consequence of apolipoprotein e genotype in late-onset Alzheimer’s disease.Proc. Natl. Acad. Sci. USA 90, 9649–9653.

    PubMed  CAS  Google Scholar 

  • Schubert D., Jin L.-W., Saitoh T., and Cole G. (1991) The regulation of amyloid beta-protein precursor secretion and its modulatory role in cell adhesion.Neuron 3, 689–694.

    Google Scholar 

  • Selkoe D. J. (1996) Amyloid-beta-protein and the genetics of Alzheimer’s disease.J. Biol. Chem. 271, 18,295–18,298.

    CAS  Google Scholar 

  • Selkoe D. J. (1994) Cell biology of the amyloid betaprotein precursors and the mechanism of Alzheimer’s disease.Ann. Rev. Cell. Biol. 10, 373–403.

    PubMed  CAS  Google Scholar 

  • Seubert P., Oltersdorf T., Lee M. G., Barbour R., Blomguist C., Davis D. L., Bryant K., Fritz L. C., Galasco D., Thal L. J., Lieberburg I., and Schenk D. B. (1993) Secretion of Β-amyloid precursor protein cleaved at the amino-terminus of the beta-amyloid peptide.Nature 361, 260–263.

    PubMed  CAS  Google Scholar 

  • Shoji M., Golde T. E., Ghiso J., Cheung T. T., Estus S., Shaffer L. M., Cai X. D., McKay D. M., Tintner R., Frangione B., and Younkin S. G. (1992) Production of the Alzheimer amyloid beta protein by normal proteolitic processing.Science 258, 126–129.

    PubMed  CAS  Google Scholar 

  • Simpkins J. W., Singh M., and Bishop J. (1994) The potential role for estrogen replacement therapy in the treatment of the cognitive decline and neurodegeneration associated with Alzheimer’s disease.Neurobiol. Aging. 15, S195-S197.

    PubMed  Google Scholar 

  • Smith C. D., Carney J. Ml., Starke-Reed P. E., Oliver C. N., Stadtman E. R., Floyd R. A., and Markesbery W. R. (1991) Excess brain protein oxidation and enzyme disfunction in normal aging and Alzheimer’s disease.Proc. Natl. Acad. Sci. USA 88, 10,540–10,543.

    CAS  Google Scholar 

  • Sohrabji F., Miranda R. C., and C. D. Toran-Allerand. (1995) Identification of a putative estrogen response element in the gene encoding brain-derived neurotrophic factor.Proc. Natl. Acad. Sci. USA 92, 11,110–11,114.

    CAS  Google Scholar 

  • Soininen H. S. and Riekkinen P. J. Sr. (1996) Apolipoprotein E, memory and Alzheimer’s disease.Trends Neurosci. 19, 224–228.

    PubMed  CAS  Google Scholar 

  • Soto C., Branes M. C., Alvarez J., and Inestrosa N. C. (1994) Structural determinants of the Alzheimer’s amyloid \-peptide.J. Neurochem. 63, 1191–1198.

    PubMed  CAS  Google Scholar 

  • Srivastava R. A., Bhasin N., and Srivastava N. (1996) Apolipoprotein E gene expression in various tissues of mouse and regulation by estrogen.Biochem. Mol. Biol. Int. 38, 91–101.

    PubMed  CAS  Google Scholar 

  • Stephenson J. (1996) More evidence links NSAID, estrogen use with reduced Alzheimer risk.JAMA. 275, 1389–1390.

    PubMed  CAS  Google Scholar 

  • Stone D. J., Rozovsky I., Morgan T. E., Anderson C. P., Hajian H., and Finch C. E. (1991) Astrocytes and microglia respond to estrogen with increased apoE mRNA in vivo and in vitro.Exp. Neurol. 143, 313–318.

    Google Scholar 

  • Subbarao K., Richardson J. S., and Ang L. C. (1990) Autopsy samples of Alzheimer’s cortex show increased peroxidation in vitro.J. Neurochem. 55, 342–345.

    PubMed  CAS  Google Scholar 

  • Sugioka K., Shimosegawa Y., and Nakano M. (1987) Estrogen as natural antioxidant of membrane phospholipid peroxidation.FEBS Lett. 210, 37–39.

    PubMed  CAS  Google Scholar 

  • Tang M.-X., Jacobs D., Stern Y., Marder K., Schofield P., Gurland B., Andrews H., and Mayeux R. (1996) Effect of estrogen during menopause on risk and age at onset of Alzheimer’s disease.Lancet. 348, 429–432.

    PubMed  CAS  Google Scholar 

  • Torand-Allerand C. D., Miranda R. C., Bentham W. D. L., Sohrabji F., Brown T. J., Hochberg R. B., and MacLusky N. J. (1992) Estrogen receptors colocalize with low-affinity nerve growth factor receptors in cholinergic neurons of the basal forebrain.Proc. Natl. Acad. Sci. USA 89, 4668–4672.

    Google Scholar 

  • Van Harren F., Van Hest A., and Heinsbrock R. P. W. (1988) Behavioral differences between male and female rats: effects of gonadal hormones on learning and memory.Neurosci. Biobehav. Res. 14, 23–33.

    Google Scholar 

  • Weisgraber K.H. (1994) Apolipoprotein E: structure-function relationships.Adv. Protein Chem. 45, 249–302.

    PubMed  CAS  Google Scholar 

  • Whitehouse P.J., Price D. L., Clark A. W., Coyle J. T., and DeLong M. R. (1981) Alzheimer disease: evidence for selective loss of cholinergic neurons in the nucleus basalis.Ann. Neurol. 10, 122–126.

    PubMed  CAS  Google Scholar 

  • Wieland N. G. (1992) Estradiol selectively regulates agonist binding sites on the N-methyl-D-aspartate receptor complex in the CAI region of the hippocampus.Endocrinology 131, 662–667.

    Google Scholar 

  • Williams C. L. and Meek W. H. (1991) The organizational effects of gonadal steroids on sexually dimorphic spatial ability.Psychoneuroendocrinology 16, 155–176.

    PubMed  CAS  Google Scholar 

  • Windier E. E., Kovanen P. J., Chao Y-S., Brown M. S., Havel R. J., and Goldstein J. L. (1980) The estradiol stimulated lipoprotein receptor of rat liver.J. Biol. Chem. 255, 10,464–10,471.

    Google Scholar 

  • Yamada T., Kondo A., Takamatsu J., Tateishi J., and Goto I. (1995) Apolipoprotein E mRNA in the brains of patients with Alzheimer’s disease.J. Neurol. Sci. 129, 56–61.

    PubMed  CAS  Google Scholar 

  • Yankner B. A. (1996) Mechanisms of neuronal degeneration in Alzheimer’s disease.Neuron 16, 921–932.

    PubMed  CAS  Google Scholar 

  • Zwain I. H., Yen S. S., and Cheng C. Y. (1997) Astrocytes cultured in vitro produce estradiol-17beta and express aromatase cytochrome P-450 (P-450 AROM) mRNA.Biochim. Biophys. Acta. 1334, 338–348.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Chile

    Nibaldo C. Inestrosa, Maria-Paz Marzolo & Andrea B. Bonnefont

Authors
  1. Nibaldo C. Inestrosa
    View author publications

    Search author on:PubMed Google Scholar

  2. Maria-Paz Marzolo
    View author publications

    Search author on:PubMed Google Scholar

  3. Andrea B. Bonnefont
    View author publications

    Search author on:PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Inestrosa, N.C., Marzolo, MP. & Bonnefont, A.B. Cellular and molecular basis of estrogen’s neuroprotection. Mol Neurobiol 17, 73–86 (1998). https://doi.org/10.1007/BF02802025

Download citation

  • Issue date:

  • DOI: https://doi.org/10.1007/BF02802025

Index Entries