Progesterone Suppresses Cholesterol Esterification in APP/PS1 mice and a cell model of Alzheimer's Disease

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.