UCSF

Sex differences have been clinically documented in numerous neurodegenerative diseases, including in Alzheimer’s disease (AD), and yet the reasons for these sex differences are not well understood. Recent studies have found that microglia, the innate immune cells of the central nervous system, are a key cell type involved in AD. Interestingly, this cell type displays sex differences in their expression profiles and function. Could these sex differences in microglia explain the sex differences seen in AD? How can we further probe these differences to better understand disease mechanisms?

In Chapter 1 of this dissertation, we broadly set the landscape of sex-differences in AD and focus specifically on the emerging evidence of microglial sex differences in both the healthy and diseased brain. We also support these previous findings through our own preliminary single-nuclei transcriptomic analysis of human AD brain tissues and characterize microglial subpopulations differentially enriched in female versus male samples.

Cellular sex differences are largely mediated through sex chromosomes and sex hormones. In Chapter 2, we focus on the sex chromosomes by studying microglial microRNAs (miRNAs) since immune-related miRNAs are highly-enriched on the X chromosome compared to the autosomal chromosomes. In Chapter 2.2, we show that microglial miRNA expression differs in male and female mice and that loss of microglial miRNAs leads to sex-specific changes in the microglial transcriptome and tau pathology. These findings suggest microglial miRNAs influence tau pathogenesis in a sex-specific manner. In Chapter 2.3, we further focus on individual microglial miRNAs by establishing a primary microglia screen to study the effects of highly-expressed microglial miRNAs on phagocytosis of E. coli particles. We found that removal of mature miRNAs in primary microglia reduced their uptake capacity, which was largely reversed by expressing individual miRNAs of the miR-17~92 cluster and its paralog, miR-106a~363 cluster encoded on the X chromosome.

Chapter 3 focuses on the sex-specific transcriptomic changes associated with microglia in AD patients with and without the R47H-TREM2 mutation, one of the strongest immune-specific risk factors for late-onset AD. We also utilized a newly-generated tauopathy knock-in mouse model expressing one allele of human TREM2 (hTREM2) with either the R47H mutation or the common variant and found R47H induced and exacerbated tau-mediated spatial memory deficits in female mice. Single-cell transcriptomic analysis of microglia from these mice also revealed transcriptomic changes induced by R47H that had significant overlaps with R47H microglia in human AD brains, including robust transcriptomic sex-differences, increases in proinflammatory cytokines, activation of Syk-Akt-signaling, and enrichment of disease-associated microglia.

Finally, in Chapter 4, we conclude on the ways these studies uncovered novel molecular pathways involved in AD pathogenesis through the lens of sex differences, and comment on future lines of investigation with the hope that such studies will lead to potential therapies that can benefit patients of both sexes.