Abstract
Prior epidemiological studies have shown decreased incidence of Alzheimer’s disease among women who were long-term users of hormone replacement therapy. In vitro studies have shown that estrogens possess antioxidant activity, protect cells from the cytotoxic effect of β-amyloid peptides, and decrease the amyloidogenic processing of the amyloid precursor protein. Animal studies have shown that estrogens promote neuronal plasticity and lead to decresed levels of cerebral β-amyloid peptide accumulation via decreased amyloidogenic processing of the amyloid precursor protein. Recently, a randomized double-blind placebo-controlled study of the effects of estrogen plus progestin treatment in women over 65 years of age found that this treatment was associated with increased incidence of probable dementia. It is not known whether this combination of hormones or the late age at which the therapy was administered was responsible for the adverse outcome.
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References
Behl C., Davis J., Lesley R., and Schubert D. (1994) Hydrogen peroxide mediates amyloid β protein toxicity. Cell 77, 817–827.
Behl C., Skutella T., Lezoualc, Post A., Widmann M., Newton C. J., and Holsboer F. (1997) Neuroprotection against oxidative stress by estrogens: structureactivity relationship. Mol. Pharmacol. 51, 535–541.
Farrer L. A., Cupples L. A., Haines J. L., Hyman B., Kukull W. A., Mayeux R., et al. (1997) Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. JAMA 278, 1349–1356.
Farr S. A., Banks W. A., and Morley J. E. (2000) Estradiol potentiates acetylcholine and glutamate-mediated post-trial memory processing in the hippocampus. Brain Res. 864, 263–269.
Gibbs R. B. (1996) Fluctuations in relative levels of choline acetyltransferase mRNA in different regions of the rat basal forebrain across the estrous cycle: effects of estrogen and progesterone. J. Neurosci. 16, 1049–1055.
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.
Gibbs R. B. (1998) Levels of trkA and BDNF mRNA, but not NGF mRNA, fluctuate across the estrous cycle and increase in response to acute hormone replacement. Brain Res. 787, 259–268.
Gouras G. K., Xu H., Gross R. S., Greenfield J. P., Hai B., Wang R., and Greengard P. (2000) Testosterone reduces neuronal secretion of Alzheimer’s beta-amyloid peptides. Proc. Natl. Acad. Sci. U.S.A. 97, 1202–1205.
Grady D., Herrington D., Bittner V., Blumenthal R., Davidson M., Hlatky M., et al. (2002) Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 288, 49–57.
Green P. S., Gridley K. E., and Simpkins J. W. (1998) Nuclear estrogen receptor-independent neuroprotection by estratrienes: a novel interaction with glutathione. Neuroscience 84, 7–10.
Green P. S. and Simpkins J. W. (2000) Neuroprotective effects of estrogens: potential mechanisms of action. Int. J. Dev. Neurosci. 18, 347–358.
Greenfield J. P., Leung L. W., Cai D., Kaasik K., Gross R. S., Rodriguez-Boulan E., et al. (2002) Estrogen lowers Alzheimer beta-amyloid generation by stimulating trans-Golgi network vesicle biogenesis. J. Biol. Chem. 277, 12,128–12,136.
Grodstein F., Manson J. E., Colditz G. A., Willett W. C., Speizer F. E., and Stampfer M. J. (2000) A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann. Intern. Med. 133, 933–941.
Henderson V. W., Paganini-Hill A., Miller B. L., Elble R. J., Reyes P. F., Shoupe D., et al. (2000) Estrogen for Alzheimer’s disease in women: randomized, double-blind, placebo-controlled trial. Neurology 54, 295–301.
Hogervorst E., Williams J., Budge M., Riedel W., and Jolles J. (2000) The nature of the effect of female gonadal hormone replacement therapy on cognitive function in post-menopausal women: a meta-analysis. Neuroscience 101, 485–512.
Hulley S., Furberg C., Barrett-Connor E., Cauley J., Grady D., Haskell W., et al. (2002) Noncardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 288, 58–66.
Jaffe A. B., Toran-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.
LeBlanc E. S., Janowsky J., Chan B. K., and Nelson H. D. (2001) Hormone replacement therapy and cognition: systematic review and meta-analysis. JAMA 285, 1489–1499.
Levin-Allerhand J., McEwen B. S., Lominska C. E., Lubahn D. B., Korach K. S., and Smith J. D. (2001) Brain region-specific up-regulation of mouse apolipoprotein E by pharmacological estrogen treatments. J. Neurochem. 79, 796–803.
Levin-Allerhand J. A., Lominska C. E., Wang J., and Smith J. D. (2002) 17α-estradiol and 17β-estradiol treatments are effective in lowering cerebral β-amyloid levels in APPSWE transgenic mice. J. Alzheim. Dis., in press.
Li R., Shen Y., Yang L. B., Lue L. F., Finch C., and Rogers J. (2000) Estrogen enhances uptake of amyloid beta-protein by microglia derived from the human cortex. J. Neurochem. 75, 1447–1454.
Manthey D., Heck S., Engert S., and Behl C. (2001) Estrogen induces a rapid secretion of amyloid beta precursor protein via the mitogen-activated protein kinase pathway. Eur. J. Biochem. 268, 4285–4291.
McEwen B. S. (2001) Invited review: Estrogens effects on the brain: multiple sites and molecular mechanisms. J. Appl. Physiol. 91, 2785–2801.
Moosmann B. and Behl C. (1999) The antioxidant neuroprotective effects of estrogens and phenolic compounds are independent from their estrogenic properties. Proc. Natl. Acad. Sci. U.S.A. 96, 8867–8872.
Mulnard R. A., Cotman C. W., Kawas C., van Dyck C. H., Sano M., Doody R., et al. (2000) Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial. Alzheimer’s Disease Cooperative Study. JAMA 283, 1007–1015.
O’Malley C. A., Hautamaki R. D., Kelley M., and Meyer E. M. (1987) Effects of ovariectomy and estradiol benzoate on high affinity choline uptake, ACh synthesis, and release from rat cerebral cortical synaptosomes. Brain Res. 403, 389–392.
Petanceska S. S., Nagy V., Frail D., and Gandy S. (2000) Ovariectomy and 17 beta-estradiol modulate the levels of Alzheimer’s amyloid beta peptides in brain. Neurology 54, 2212–2217.
Pike C. J., Burdick D., Walencewicz A. J., Gabe C. G., and Cotman C. W. (1993) Neurodegeneration induced by β-amyloid peptides in vitro: the role of peptide assembly state. J. Neurosci. 13, 1676–1687.
Pike C. J. (1999) Estrogen modulates neuronal Bcl-xL expression and beta-amyloid-induced apoptosis: relevance to Alzheimer’s disease. J. Neurochem. 72, 1552–1563.
Schneider L. S., Farlow M. R., Henderson V. W., and Pogoda J. M. (1996) Effects of estrogen replacement therapy on response to tacrine in patients with Alzheimer’s disease. Neurology 46, 1580–1584.
Sherwin B. B. (1994) Estrogenic effects on memory in women. Ann. N.Y. Acad. Sci. 743, 213–230.
Shumaker S. A., Reboussin B. A., Espeland M. A., Rapp S. R., McBee W. L., Dailey M., et al. (1998) The Women’s Health Initiative Memory Study (WHIMS): a trial of the effect of estrogen therapy in preventing and slowing the progression of dementia. Control Clin. Trials 19, 604–621.
Shumaker S. A., Legault C., Thal L., Wallace R. B., Ockene J. K., Hendrix S. L., et al. (2003) 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 289, 2651–2662.
Stone D. J., Rozovsky I., Morgan T. E., Anderson C. P., and Finch C. E. (1998) Increased synaptic sprouting in response to estrogen via an apolipoprotein E-dependent mechanism: implications for Alzheimer’s disease. J. Neurosci. 18, 3180–3185.
Tang M. X., Jacobs D., Stern Y., Marder K., Schofield P., Gurland B., et al. (1996) Effect of oestrogen during menopause on risk and age at onset of Alzheimer’s disease. Lancet 348, 429–432.
Wang P. N., Liao S. Q., Liu R. S., Liu C. Y., Chao H. T., Lu S. R., et al. (2000) Effects of estrogen on cognition, mood, and cerebral blood flow in AD: a controlled study. Neurology 54, 2061–2066.
Xu H., Gouras G. K., Greenfield J. P., Vincent B., Naslund J., Mazzarelli L., et al. (1998) Estrogen reduces neuronal generation of Alzheimer beta-amyloid peptides. Nat. Med. 4, 447–451.
Zheng H., Xu H., Uljon S. N., Gross R., Hardy K., Gaynor J., et al. (2002) Modulation of A beta peptides by estrogen in mouse models. J. Neurochem. 80, 191–196.
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Smith, J.D., Levin-Allerhand, J.A. Potential use of estrogen-like drugs for the prevention of Alzheimer’s disease. J Mol Neurosci 20, 277–281 (2003). https://doi.org/10.1385/JMN:20:3:277
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DOI: https://doi.org/10.1385/JMN:20:3:277