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Estrogen reduces neuronal generation of Alzheimer β-amyloid peptides

Abstract

Alzheimer's disease (AD) is characterized by the accumulation of cerebral plaques composed of 40- and 42-amino acid β-amyloid (Aβ) peptides, and autosomal dominant forms of AD appear to cause disease by promoting brain Aβ accumulation. Recent studies indicate that postmenopausal estrogen replacement therapy may prevent or delay the onset of AD. Here we present evidence that physiological levels of 17β-estradiol reduce the generation of Aβ by neuroblastoma cells and by primary cultures of rat, mouse and human embryonic cerebrocortical neurons. These results suggest a mechanism by which estrogen replacement therapy can delay or prevent AD.

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References

  1. Glenner, G. & Wong, C.W. Alzheimer's disease: Initial report of the purification and characteristics of a novel cerebrovascular amyloid protein. Biochem. Bbphys. Res. Commun. 122, 885–890 (1984).

    Article  Google Scholar 

  2. Masters, C.L. et al. Amyloid plaque core protein in Alzheimer's disease and Down's syndrome. Proc. Natl. Acad. Sci. U.S.A. 82, 4245–4249 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Haass, C., Hung, A.Y., Schlossmacher, M.G., Teplow, D.B. & Selkoe, D.J. β-amyloid peptide and a 3-kDa fragment are derived by distinct cellular mechanisms. J. Biol. Chem. 268, 3021–3024 (1993).

    CAS  PubMed  Google Scholar 

  4. Haass, C. & Selkoe, D.J. Cellular processing of β-amyloid precursor protein and genesis of the amyloid-β peptide. Cell 75, 1039 42 (1993).

    Article  CAS  PubMed  Google Scholar 

  5. Jaffe, A.B., Toran-Allerand, C.D., Greengard, P. & Gandy, S.E. Estrogen regulates metabolism of Alzheimer amyloid β precursor protein. J. Biol. Chem. 269, 13065–13068 (1994).

    CAS  PubMed  Google Scholar 

  6. Wang, R., Sweeney, D., Gandy, S.E. & Sisodia, S.S. The profile of soluble amyloid β protein in cultured cell media. J. Biol. Chem. 271, 31894–31902 (1996).

    Article  CAS  PubMed  Google Scholar 

  7. Ausubel, F.M. et al. in Short Protocols in Molecular Biology, Second Edition, (John Wiley and Sons, New York, (1992).

    Google Scholar 

  8. Scheuner, D. et al. Secreted amyloid β-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nature Med. 2, 864–870 (1996).

    Article  CAS  PubMed  Google Scholar 

  9. Borchelt, D.R. et al. Familial Alzheimer's disease-linked presenilin 1 variants elevate Aβ1 -42/1 -40 ratio in vitro and in vivo. Neuron 17, 1005–1013 (1996).

    Article  CAS  PubMed  Google Scholar 

  10. Duff, K. et al. Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1. Nature 383, 710–713 (1996).

    Article  CAS  PubMed  Google Scholar 

  11. Citron, M. et al. Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice. Nature Med. 3, 67–72 (1997).

    Article  CAS  PubMed  Google Scholar 

  12. Iwatsubo, T. et al. Visualization of Aβ 42(43) and Aβ 40 in senile plaques with end-specific Aβ monoclonals: evidence that an initially deposited species is Aβ 42(43). Neuron 13, 45–53 (1994).

    Article  CAS  PubMed  Google Scholar 

  13. Perez-Tur, J. et al. A mutation in Alzheimer's disease destroying a splice acceptor site in the presenilin-1 gene. Neuroreport 7, 297–301 (1995).

    Article  CAS  PubMed  Google Scholar 

  14. Barelli, H. et al. Characterization of new polyclonal antibodies specific for 40 and 42 amino acid-long amyloid β peptides: their use to examine the cell biology of presenilins and the immunohistochemistry of sporadic and cerebral amyloid angiopathy cases. Mol. Med. 3, 695–707 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kim, K.S. et al. Detection and quantitation of amyloid β-peptide with monoclonal antibodies. Neurosci. Res. Commun. 7, 113–122 (1990).

    CAS  Google Scholar 

  16. Lu, B., Yokoyama, M., Dreyfus, C.F. & Black, I.B. Depolarizing stimuli regulate nerve growth factor gene expression in cultured hippocampal neurons. Proc. Natl. Acad. Sci. U.S.A. 88, 6289–6292 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Simons, M. et al. Amyloidogenic processing of the human amyloid precursor protein in primary cultures of rat hippocampal neurons. J. Neurosci. 16, 899–908 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Feingold, K.R., Galvin, L.A., Schambelan, M. & Sebastian, A. . in Cecil's Essentials of Medicine (eds. Andreoli, T. E., Carpenter, C. C. J., Plum, F. & Smith, L. H.) 478 (W. B. Saunders Co., Philadelphia, (1990).

    Google Scholar 

  19. Tang, M. et al. Effect of oestrogen during menopause on risk and age of onset of Alzheimer's disease. Lancet 348, 429–432 (1996).

    Article  CAS  PubMed  Google Scholar 

  20. Luine, V. Estradiol increases choline acetyltransferase activity in specific basal forebrain nuclei and projection areas of female rats. Exp. Neurol. 89, 484–490 (1985).

    Article  CAS  PubMed  Google Scholar 

  21. Woolley, C.S. & McEwen, B.S. Roles of estradiol and progesterone in regulation of hippocampal dendritic spine density during the estrous cycle in the rat. J. Comp. Neurol. 336, 293–306 (1993).

    Article  CAS  PubMed  Google Scholar 

  22. Woolley, C.S., Weiland, N.G. McEwen, B.S. & Schwartzkroin, P. A. Estradiol increases the sensitivity of hippocampal CA1 pyramidal cells to NMDA receptor-mediated synaptic input: correlation with dendritic spine density. J. Neurosci. 17, 1848–1859 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Toran-Allerand, C.D. The estrogen/neurotrophin connection during neural development: is co-localization of estrogen receptors with the neurotrophins and their receptors biologically relevant?. Dev. Neurosci. 18, 36–48 (1996).

    Article  CAS  PubMed  Google Scholar 

  24. Behl, C., Widman, M., Trapp, T. & Holsboer, F. 17-beta estradiol protects neurons from oxidative stress-induced cell death in vitro. Biochem. Biophys. Res. Commun. 216, 473–482 (1995).

    Article  CAS  PubMed  Google Scholar 

  25. Larson, G.H. & Wise, P.M. Constitutive and regulated prolactin secretion: effects of estradiol. Biology of Reproduction. 50, 357–362 (1994).

    Article  CAS  PubMed  Google Scholar 

  26. Scammell, J.C., Burrage, T.C. & Dannies, P.S. Hormonal induction of secretory granules in a pituitary tumor cell line. Endocrinology 119, 1543–1548 (1986).

    Article  CAS  PubMed  Google Scholar 

  27. Xu, H. et al. Generation of Alzheimer β-amyloid protein in the trarns-Golgi network in the apparent absence of vesicle formation. Proc. Natl. Acad. Sci. U.S.A. 94, 3748–3752 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Xu, H., Greengard, P. & Gandy, S. Regulated formation of Golgi secretory vesicles containing Alzheimer β-amyloid precursor protein. J. Biol. Chem. 270, 23243–23255 (1995).

    Article  CAS  PubMed  Google Scholar 

  29. Xu, H., Sweeney, D., Greengard, P. & Gandy, S. Metabolism of Alzheimer β-amyloid precursor protein: regulation by protein kinase A in intact cells and in a cell-free system. Proc. Natl. Acad. Sci. U.S.A. 93, 4081–4083 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Vincent, B., Beaudet, A., Dauch, P., Vincent, J.P. & Checler, F. Distinct properties of neuronal and astrocytic endopeptidase 3. 4.24.16: a study on differentiation, sub-cellular distribution, and secretion processes. J. Neurosci. 16, 5049–5059 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Buxbaum, J.D. et al. Processing of Alzheimer beta/A4 amyloid precursor protein: Modulation by agents that regulate protein phosphorylation. Proc. Natl. Acad. Sci. U.S.A. 87, 6003–6006 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Thinakaran, G. et al. Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron 17, 181–190 (1996).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Desdouits, F., Buxbaum, J.D., Desdouits-Magnen, J., Nairn, A.C. & Greengard, P. Amyloid β peptide formation in cell-free preparations. J. Biol. Chem. 271, 24670–24674 (1996).

    Article  CAS  PubMed  Google Scholar 

  35. Weidemann, A. et al. Identification, biogenesis and localization of precursors of Alzheimer's disease A4 amyloid protein. Cell 57, 115–126 (1989).

    Article  CAS  PubMed  Google Scholar 

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Xu, H., Gouras, G., Greenfield, J. et al. Estrogen reduces neuronal generation of Alzheimer β-amyloid peptides. Nat Med 4, 447–451 (1998). https://doi.org/10.1038/nm0498-447

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