Mechanisms of microglial-mediated sex-based differences in tauopathy

PROJECT SUMMARY/ABSTRACT Microglia, the resident innate immune cells in the brain, are increasingly recognized as key players in the pathogenesis of tauopathies like Alzheimer’s disease (AD) and related dementias (ADRDs). Across humans and mouse models of ADRDs, sex-based differences exist in the prevalence and pathophysiology of disease, but the mechanisms by which sex-based biology contributes to neurodegeneration are understudied. Microglia are known to exhibit sex-based differences across a variety of diseases. The Condello Lab found that upon microglial depletion, female mice exhibit a sex-specific functional rescue and extended survival in a mouse model of tauopathy (Tg2541), thus microglia mediate some sex-based differences in tauopathy. Interestingly, inflammatory phenotypes in microglia can be modulated by estrogens and recent studies have shown that age of onset of menopause can affect levels of tau burden, thus levels of gonadal hormones may contribute to tau deposition. With age as a significant risk factor for the pathogenesis of tauopathies and the changes in gonadal hormones over the course of aging (e.g., menopause and andropause), we hypothesize that gonadal hormones contribute to sex-based differences in tauopathy through their activity on microglia. The objectives of this proposal are to determine the effects of gonadal hormones on (1) sex-based transcriptomic and morphologic signatures of microglia and (2) sex-based differences in disease phenotypes of tauopathy. Using the Tg2541 transgenic mouse model of tauopathy and wildtype controls, mice will undergo gonadectomies to deplete the endogenous sources of estradiol, progesterone, and testosterone; sham surgeries will be performed as control. In Aim 1, the effects of gonadal hormones on microglial cell states will be explored using a combination of single- cell RNA sequencing to assess transcriptionally distinct subtypes of microglia and spatial transcriptomics to assess microglial phenotypes across brain regions and in relation to tau deposition. Other microglial features that exhibit sex-based differences, such as morphology, will be assessed via immunofluorescent staining. In Aim 2, time course and longitudinal studies will be performed to assess the impact of gonadal hormones on the progression of disease pathology, behavior, and survival in the Tg2541 model. Completion of this proposal will shed light on how sex-based biology contributes to the microglial-mediated sex-based differences in tauopathy and provide a rich transcriptomic dataset that can be leveraged for further mechanistic studies. An increased understanding of the impact of gonadal hormones on microglia and tauopathy will be critically important for the design of microglia-specific therapeutics for ADRDs that can be effective in males and females. The UCSF Institute for Neurodegenerative Diseases (IND) provides an ideal environment for the completion of the proposed work, offering rigorous training in animal models, bioinformatics, and confocal microscopy, as well as support for professional development. Furthermore, the sponsors are committed to the comprehensive training plan we have developed that will prepare me for my career as a scientific leader in biomedical research.