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. Overall design: 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.