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Abstract
"Females who enter menopause prematurely
via bilateral ovariectomy (surgical menopause) have a significantly
increased risk
for cognitive decline and dementia. To help
elucidate the mechanisms underlying this phenomenon, we used an animal
model of
surgical menopause, long-term (10-week) bilateral
ovariectomy in female rats. Herein, we demonstrate that long-term
oestrogen
deprivation dramatically increases sensitivity of
the normally resistant hippocampal CA3 region to ischaemic stress, an
effect
that was gender-specific, as it was not observed in
long-term orchiectomized males. Furthermore, the enhanced damage to the
CA3 region correlated with a worse cognitive
outcome after ischaemic stress. Long-term ovariectomized rats also
displayed
a robust hyperinduction of Alzheimer’s
disease-related proteins in the CA3 region and a switch in amyloid
precursor protein
processing from non-amyloidogenic to amyloidogenic
following ischaemic stress CA3 hypersensitivity also extended to an
Alzheimer’s
disease-relevant insult, as the CA3 region of
long-term ovariectomized rats was profoundly hypersensitive to the
neurotoxic
effects of amyloid-β1–42, the most amyloidogenic
form of the amyloid-β peptide. Additional studies revealed that CA3
region
hypersensitivity, Alzheimer’s disease-related
protein induction, and amyloidogenesis are mediated by a NADPH
oxidase/superoxide/c-Jun
N-terminal kinase/c-Jun signalling pathway,
involving both transcriptional and post-translational mechanisms. In
addition,
while 17β-oestradiol replacement at the end of the
long-term oestrogen deprivation period could not prevent CA3
hypersensitivity
and amyloidogenesis, if 17β-oestradiol was
initiated at the time of ovariectomy and maintained throughout the
10-week oestrogen
deprivation period, it completely prevented these
events, providing support for the ‘critical window’ hypothesis for
oestrogen
replacement therapy benefit. Collectively, these
findings may help explain the increased risk of cognitive decline and
dementia
observed in women following surgical menopause, and
they provide increased support that early 17β-oestradiol replacement is
critical in preventing the negative neural effects
associated with bilateral ovariectomy.
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