Modulation of A(beta) peptides by estrogen in mouse models.
Clinical studies have shown that estrogen deprivation through menopause is a risk factor in both the initiation and progression of Alzheimer's disease (AD) and that estrogen replacement therapy may be protective. One of the major pathological features in the human AD brain is the senile plaque, a proteinaceous structure composed mainly of heterogeneous peptides collectively known as A-beta (A(beta)). In vitro studies have linked estrogen with A(beta) modulation, suggesting that one-way that estrogen depletion at menopause may exacerbate the features of AD is through A(beta) accumulation. To test this, two studies were performed on transgenic models of amyloidosis. Firstly, transgenic mice without detectable amyloid aggregates were subjected to ovariectomy and estradiol supplementation, and A(beta) levels were assessed. Secondly, the effects of estrogen modulation were assessed in mice at an age when plaques would be forming initially. Overall, A(beta) levels were higher in estrogen-deprived mice than intact mice, and this effect could be reversed through the administration of estradiol. These data suggest that, in vivo, estrogen depletion leads to the accumulation of A(beta) in the CNS, which can be reversed through replacement of estradiol. These results provide evidence that post-menopausal estrogen depletion may be linked to an increased risk of AD through A(beta) modulation.
Zheng
H
H
Huffington Center on Aging, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Xu
H
H
Uljon
S N
SN
Gross
R
R
Hardy
K
K
Gaynor
J
J
Lafrancois
J
J
Simpkins
J
J
Refolo
L M
LM
Petanceska
S
S
Wang
R
R
Duff
K
K
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D004958:Estradiol / Q000494:pharmacology*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics; D010052:Ovariectomy; D010446:Peptide Fragments / Q000378:metabolism; D053764:Presenilin-1
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D004958:Estradiol