Overexpression of PGRMC2 in astrocytes improved cognitive function in a mouse model of Alzheimer’s disease by modulating neuroinflammation

Recent studies have identified persistent immune inflammation as the third core pathological change in Alzheimer’s disease (AD). Progesterone receptor membrane component 2 (PGRMC2) is a member of the membrane-associated progesterone receptor family. This study aimed to investigate the effects of the expression of PGRMC2 in astrocytes in an AD mouse model. PGRMC2 overexpression in astrocytes was induced in male APPswe/PSEN1dE9 transgenic (AD) mice and C57BL/6J wild-type mice via an adeno-associated virus vector. The Morris water maze and Y-maze tests were used to evaluate spatial learning, spatial memory, and working memory. Cortical thickness and hippocampal volume were evaluated via brain MRI scans. Protein and mRNA levels were analyzed using Western blotting, qPCR, immunohistochemistry, and immunofluorescence techniques. PGRMC2 expression was significantly elevated in astrocytes in the AD mouse brain tissue. Learning and memory improved, brain atrophy was alleviated, and neuronal loss was reduced, but Aβ1–42 deposition was unaffected. These changes correlated with alterations in NF-κB signaling and shifts in astrocyte phenotypes, including reduced A1 activation and enhanced A2 polarization. PGRMC2 overexpression in astrocytes exerts neuroprotective effects on AD mice by altering astrocyte polarization and inflammatory responses; however, the present study does not establish causality in vivo.