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Progesterone Suppresses Cholesterol Esterification in APP/PS1 mice and a cell model of Alzheimer's Disease
Wenjing Shi1, Hang Wu2, Sha Liu3
1Department of Pharmacology, Hebei Medical University, Shijiazhuang 050017, Hebei Province, China; Department of Pharmacy, Hebei General Hospital, Shijiazhuang 050051, Hebei Province, China.
Aims:
Cholesteryl ester(CE), generated from the mitochondria associated membrane (MAM), is involved in the pathogenesis of Alzheimer's Disease (AD). In theory, the different neuroprotective effects of progesterone in AD are all linked to MAM, yet the effect on cholesterol esterification has not been reported. Therefore, this study was aimed to investigate the regulation of progesterone on intracerebral CE in AD models and the underlying mechanism.
Methods:
APP/PS1 mice and AD cell model induced by Aβ 25-35 were selected as the research objects. APP/PS1 mice were daily administrated intragastrically with progesterone and The Morris Water Maze test was performed to detect the learning and memory abilities. Intracellular cholesterol was measured by Cholesterol/Cholesteryl Ester Quantitation Assay. The structure of MAMs were observed with transmission electron microscopy. The expression of acyl-CoA: cholesterol acyltransferase 1 (ACAT1), ERK1/2 and p-ERK1/2 were detected with western blotting, immunohistochemistry or immunofluorescence.
Results:
Progesterone suppressed the accumulation of intracellular CE, shortened the length of abnormally prolonged MAM in cortex of APP/PS1 mice. Progesterone decreased the expression of ACAT1, which could be blocked by progesterone receptor membrane component 1 (PGRMC1) inhibitor AG205. The ERK1/2 pathway maybe involved in the progesterone mediated regulation of ACAT1 in AD models, rather than the PI3K/Akt and the P38 MEPK pathways.
Significance:
The results supported a line of evidence that progesterone regulates CE level and the structure of MAM in neurons of AD models, providing a promising treatment against AD on the dysfunction of cholesterol metabolism.
Insights
Progesterone reduces cholesteryl ester accumulation and improves mitochondrial-associated membrane structure in Alzheimer
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Cholesteryl ester (CE) accumulation in mitochondria-associated membranes (MAM) is implicated in Alzheimer's Disease (AD) pathogenesis.
- Progesterone's neuroprotective effects in AD are linked to MAM, but its impact on cholesterol esterification remains unclear.
Purpose of the Study:
- To investigate how progesterone regulates intracerebral CE levels in AD models.
- To elucidate the underlying molecular mechanisms of progesterone's action on cholesterol metabolism in AD.
Main Methods:
- Utilized APP/PS1 mice and Aβ 25-35 induced AD cell models.
- Administered progesterone and assessed cognitive function using the Morris Water Maze test.
- Quantified intracellular cholesterol, examined MAM structure via electron microscopy, and analyzed protein expression (ACAT1, ERK1/2) using western blotting and immunohistochemistry.
Main Results:
- Progesterone suppressed intracellular CE accumulation and normalized MAM structure in AD mouse models.
- Progesterone decreased ACAT1 expression, an effect potentially mediated by the progesterone receptor membrane component 1 (PGRMC1).
- The ERK1/2 pathway, not PI3K/Akt or P38 MAPK, appears involved in progesterone's regulation of ACAT1.
Conclusions:
- Progesterone effectively modulates CE levels and MAM structure in neurons of AD models.
- These findings suggest progesterone as a potential therapeutic agent for AD by targeting cholesterol metabolism dysfunction.
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