The LH receptor regulates hippocampal spatial memory and restores dendritic spine density in ovariectomized APP/PS1 AD mice
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Abstract
Activation of the luteinizing hormone receptor (LHCGR) rescues spatial memory function and spine density losses associated with gonadectomy and high circulating gonadotropin levels in females. However, whether this extends to the AD brain or the mechanisms that underlie these benefits remain unknown. To address this question, we delivered the LHCGR agonist human chorionic gonadotropin (hCG) intracerebroventricularly (ICV), under reproductively intact and ovariectomized conditions to mimic the post-menopausal state in the APP/PS1mouse brain. Cognitive function was tested using the Morris water maze task, and hippocampal dendritic spine density, Aβ pathology, and signaling changes associated with these endpoints were determined to address mechanisms. Here we show that central LHCGR activation restored function in ovariectomized APP/PS1 female mice to wild-type levels without altering Aβ pathology. LHCGR activation increased hippocampal dendritic spine density regardless of reproductive status, and this was mediated by BDNF-dependent and independent signaling. We also show that ovariectomy in the APP/PS1 brain elicits an increase in peripherally derived pro-inflammatory genes which are inhibited by LHCGR activation. This may mediate reproductive status specific effects of LHCGR agonism on cognitive function and BDNF expression. Together, this work highlights the relevance of the LHCGR on cognition and its therapeutic potential in the “menopausal” AD brain.
Article activity feed
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activation toinhibition
Typo? “...activation to inhibition…”
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independently of Aβ pathology regulation
Even though the Aβ plaque number and area weren’t considerably different according to Thioflavin S imaging, do you think you could have seen a difference in the soluble Aβ40 or Aβ42 measurements if you used the hippocampal tissue?
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differentially expressed genes
Do you intend on making the raw data publicly available in the future?
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between the these comparisons
Typo? “...between these comparisons…”
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i-phathway software
Typo? “...i-pathway software…”
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40X magnification ImageJ
Typo? “...40X magnification. ImageJ was…”
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eported that the expression ofLH within the brain is inverse to systemic levels
This inverse relationship is incredibly fascinating! Are you aware of the specifics of the correlation between cognitive function in ovariectomized AD mice that don’t undergo pharmacological inhibition of systemic gonadotropin levels? (I.e. Did brain LH levels increase as cognitive function symptoms worsen or did cognitive function issues occur once a brain LH threshold was reached?) I could imagine that continuous monitoring of systemic LH levels could potentially serve as a proxy for cognitive function issues in menopausal women if this inverse relationship is taken into account?
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The authors aimed to determine whether the central activation of the luteinizing hormone via hCG in ovariectomized AD (APP/PSI) mice impacts cognitive function (Morris water maze test), Aβ pathology (Aβ plaque number and area from Thioflavin S imaging and soluble Aβ levels from cortical tissue), hippocampal dendritic spine density (Golgi staining) and/or signaling changes (RNA-seq to see differential gene expression).
Although the authors did present compelling evidence supporting the potential that LHCGR activation improves spatial memory and increases dendritic spine density in OVX PP/PSI mice, the evidence is based on an underlying assumption that the results are due to the activation of LHCGR rather than the potential impact of hCG being present centrally. It would have been helpful to compare the results of centrally delivering hCG …
The authors aimed to determine whether the central activation of the luteinizing hormone via hCG in ovariectomized AD (APP/PSI) mice impacts cognitive function (Morris water maze test), Aβ pathology (Aβ plaque number and area from Thioflavin S imaging and soluble Aβ levels from cortical tissue), hippocampal dendritic spine density (Golgi staining) and/or signaling changes (RNA-seq to see differential gene expression).
Although the authors did present compelling evidence supporting the potential that LHCGR activation improves spatial memory and increases dendritic spine density in OVX PP/PSI mice, the evidence is based on an underlying assumption that the results are due to the activation of LHCGR rather than the potential impact of hCG being present centrally. It would have been helpful to compare the results of centrally delivering hCG and LH in order to identify similarities which may be due to LHCGR activation versus impacts on cognitive function or spine density that may be due to the central presence of LH or hCG and an unknown alternative interaction.
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