Early Modulation of the Gut Microbiome by Female Sex Hormones Alters Amyloid Pathology and Microglial Function

It is well-established that women are disproportionately affected by Alzheimer’s disease (AD). The mechanisms underlying this sex-specific disparity are not fully understood, but several factors that are often associated-including interactions of sex hormones, genetic factors, and the gut microbiome-likely contribute to the disease's etiology. Here, we have examined the role of sex hormones and the gut microbiome in mediating A amyloidosis and neuroinflammation in APPPS1-21 mice. We report that postnatal gut microbiome perturbation in female APPPS1-21 mice leads to an elevation in levels of circulating estradiol. Early stage ovariectomy (OVX) leads to a reduction of plasma estradiol that is correlated with a significant alteration of gut microbiome composition and reduction in A pathology. On the other hand, supplementation of OVX-treated animals with estradiol restores A burden and influences gut microbiome composition. The reduction of A pathology with OVX is paralleled by diminished levels of plaque-associated MGnD-type microglia while estradiol supplementation of OVX-treated animals leads to a restoration of activated microglia around plaques. In summary, our investigation elucidates the complex interplay between sex-specific hormonal modulations, gut microbiome dynamics, metabolic perturbations, and microglial functionality in the pathogenesis of Alzheimer's disease. Total RNA was extracted from the dorsal cerebral cortex using Trizol reagent, as per the protocol by Dodiya et al. [9], and cleaned with the RNAeasy Micro kit (Qiagen). Quality assessment was done with an Agilent Bioanalyzer. RNA-seq library preparations and sequencing were performed using an Illumina HiSeq4000 at The University of Chicago Genomics Core Facility. The data were collected in FASTQ format for bioinformatic analysis.