Sex-specific impact of brain estrogen deficiency on the hippocampal transcriptome changes and memory deficits in brain-specific aromatase knockout mouse models

Background: Nearly two-thirds of Americans with Alzheimer's disease (AD) are women, however, the molecular mechanisms underlying this sex difference in AD vulnerability remain unclear. Prior research has reported that women with AD have lower brain estrogen. Yet, how estrogen deficiency modulates this sex difference in AD is not well understood. Aromatase, the key enzyme for estrogen biosynthesis, is expressed in both neurons and astrocytes of the brain, with high levels in the hippocampus. To explore the underlying mechanism of estrogen deficiency in sex-specific AD vulnerability, we generated mouse models with brain-specific aromatase knockout (bArKO) and whole-body total aromatase knockout (tArKO). Method: We performed a series of memory and behavior tests including spontaneous alternation, social interaction, and tail suspension tests on 6- and 19-month-old bArKO and tArKO mice with both sexes (n=10/group). Hippocampus tissues from these mice (n=3~4) were collected for bulk RNA-seq and qPCR. Serum and tissue estrogen were measured using liquid chromatography-mass spectrometry. Result: Aromatase deletion decreased brain estrogen levels in bArKO mice and circulating and brain estrogen levels in tArKO mice. Impairments of spatial working memory and social interaction behavior were found in 19-month-old female bArKO and tArKO mice. Female tArKO mice also displayed depression-like behavior at 6- and 19-month-old. Bulk RNA-seq showed differentially expressed genes associated with glia and neurons (e.g., Tenm4, Col1a1, Ogn, Dcn, Slc17a6, and Ccn2) in aged female bArKO mice. Conclusion: Our findings provide novel mechanisms that link estrogen deficiency to sex-specific transcriptome changes in the hippocampus and memory loss in aged female mice. Future studies will focus on defining impact of estrogen signaling deficiency on AD mouse models and identifying druggable targets to inform the development of new therapeutic strategies for the prevention and treatment of AD.