| dc.description.abstract | Neuroinflammation and brain iron dyshomeostasis are key features of several neurodegenerative diseases, including Alzheimer’s disease (AD). Specifically, microglial activation and iron load have been recently appreciated as significant AD hallmarks. In vitro studies show that microglia preferentially upregulate iron importer, divalent metal transporter 1 (DMT1, gene name Slc11a2) in response to inflammatory stimuli, and iron import can augment cellular inflammation, suggesting a feed-forward loop between iron import mechanisms and inflammatory signaling. However, it is not understood how microglial iron import mechanisms directly contribute to inflammatory signaling and disease in vivo. The studies in this dissertation determined the effects of knocking down microglial iron import gene Slc11a2 on the inflammatory response and AD-related disease progression. A novel mouse model of tamoxifen-inducible, microglial-specific Slc11a2 knockdown was generated using Cx3cr1Cre-ERT2 mice. Transgenic Slc11a2flfl;Cx3cr1Cre-ERT2 mice given tamoxifen or corn oil were administered intraperitoneal saline or lipopolysaccharide (LPS), and sickness behavior, plasma cytokines, and microglial gene expression were measured. There was a significant LPS-induced upregulation in Slc11a2 in male, but not female, microglia. Microglial Slc11a2 knockdown resulted in a significant blunting of LPS-induced pro-inflammatory gene expression only in male microglia, which was associated with a decrease in systemic inflammatory cytokines in the males. Bulk transcriptional analyses revealed further changes in gene expression, as male Slc11a2 knockdown microglia displayed upregulations in anti-inflammatory, iron-releasing, and antioxidant markers post-LPS. These cellular changes in the male Slc11a2 knockdown mice were mirrored in significant improvements in LPS-induced sickness scores. Studies conducted in the APP/PS1 model of AD determined the effects of Slc11a2 knockdown on cognitive function. Slc11a2flfl;Cx3cr1Cre-ERT2;APP/PS1+ or control mice were given tamoxifen or corn oil at 5-6 months of age and assessed for behavioral analyses at 12-15 months. APP/PS1 Slc11a2 knockdown female mice displayed a significant worsening of memory function in Morris water maze and a fear conditioning assay, along with significant hyperactivity in several tasks compared to controls. This work suggests a sex-specific role for microglial Slc11a2 in mediating acute pro-inflammatory responses and chronic disease processes, providing novel insights into the roles that microglia play in disease. | |
