Brain endogenous estrogen levels determine responses to estrogen replacement therapy via regulation of BACE1 and NEP in female Alzheimer's transgenic mice

Mol Neurobiol. 2013 Jun;47(3):857-67. doi: 10.1007/s12035-012-8377-3. Epub 2012 Nov 20.

Abstract

Estrogens have been found to improve memory and reduce risk of dementia, although conflicting results such as failure of estrogen replacement therapy for treatment of Alzheimer's disease (AD) also has been reported. Only recently, our published human brain studies showed a depletion of brain estrogen in women with AD, while other studies have demonstrated cognitive impairment believed to be caused by inhibition of endogenous estrogen synthesis in females. To investigate whether the shortage of brain estrogen alters the sensitivity of response to estrogen replacement therapy, we have used genetic and surgical animal models to examine the response of estrogen treatment in AD neuropathology. Our studies have shown that early treatment with 17β-estradiol (E2) or genistein could reduce brain amyloid levels by increasing Aβ clearance in both APP23 mice with genetic deficiency of aromatase (APP/Ar(+/-)), in which the brains contain nondetectable levels of estrogen, and in APP23 mice with an ovariectomy (APP/OVX), in which the brains still contain certain levels of estrogen. However, only APP/Ar(+/-) mice showed a great reduction in brain amyloid plaque formation after E2 or genistein treatment along with downregulation of β-secretase (BACE1) mRNA and protein expression. Our results suggest that early and long-term usage of E2 and/or genistein may prevent AD pathologies in a dependent manner on endogenous brain estrogen levels in aged females.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Amyloid Precursor Protein Secretases / genetics
  • Amyloid Precursor Protein Secretases / metabolism*
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Aromatase / metabolism
  • Aspartic Acid Endopeptidases / genetics
  • Aspartic Acid Endopeptidases / metabolism*
  • Brain / drug effects
  • Brain / metabolism*
  • Brain / pathology
  • Estradiol / pharmacology
  • Estradiol / therapeutic use
  • Estrogen Replacement Therapy*
  • Estrogens / metabolism*
  • Female
  • Gene Expression Regulation / drug effects
  • Genistein / pharmacology
  • Genistein / therapeutic use
  • Humans
  • Mice
  • Mice, Transgenic
  • Neprilysin / metabolism*
  • Ovariectomy
  • Plaque, Amyloid / metabolism
  • Plaque, Amyloid / pathology
  • Proteolysis / drug effects
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism

Substances

  • Amyloid beta-Peptides
  • Estrogens
  • RNA, Messenger
  • Estradiol
  • Genistein
  • Aromatase
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • Bace1 protein, mouse
  • Neprilysin