Sex differences in the microRNA-mediated regulation of microglia function in a tauopathy mouse model Lay Kodama1,2,3, Jon I. Etchegaray1, Elmer Guzman4, Yaqiao Li1, Yungui Zhou1, David Le1, Joe Udeochu1, Faten Sayed1,2,3, Kenneth S. Kosik4, Li Gan1,2,3 1Gladstone Institutes, San Francisco; 2Neuroscience Graduate Program, University of California, San Francisco; 3Department of Neurology, University of California, San Francisco; 4University of California, Santa Barbara
Tauopathies, such as Alzheimer's Disease (AD), are neurodegenerative diseases whose pathological hallmarks include neuroinflammation and tau aggregates. Microglia are the resident innate immune cells of the central nervous system (CNS) and their dysregulation is implicated in tauopathies. Therefore, it is necessary to understand how molecular pathways regulate the CNS immune system. MicroRNAs (miRNAs) are a class of small, noncoding RNAs that target multiple mRNAs to modulate many pathways. Because of this unique property, miRNAs are ideal for uncovering new networks that modulate immune function in disease. Moreover, studies have shown sex differences in the expression of miRNAs in AD patients and a sex-bias in the risk of developing the disease. Hence, we hypothesize that sexually dimorphic miRNAs are important for regulating microglia function and tau pathology. In this study, we show loss of microglial miRNAs exacerbates tau aggregation in male but not in female tauopathy mice. Morphologically, Dicer deficient microglia from male tauopathy mice are more activated compared to females from the same genotype. To determine which miRNAs have sex-specific effects in microglia, we did miRNA sequencing of adult microglia isolated from PS19 and nontransgenic mice. Our preliminary analysis shows much of the variation between samples can be explained by the sex of the mice. Ingenuity Pathway Analysis shows male microglia express higher levels of miRNAs that target endocytosis signaling compared to female microglia. Previous studies have shown microglia are able to phagocytose tau in vitro and in vivo, a process that may propagate tau pathology. To probe miRNAs involved in tau aggregation, we aim to study candidate miRNAs in primary microglia and how they modulate tau phagocytosis. Completion of this study will elucidate the regulation of microglia function by miRNAs, yield insights into new pathways regulating microglia in tauopathies, and uncover potential targets for miRNA-based therapeutics.
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