Chronic stress has been associated with promoting neurodegenerative diseases, such as Alzheimer’s disease (AD), through dysregulating the Hypothalamic-Pituitary-Adrenal (HPA) axis and increasing cortisol levels. The cellular action of cortisol is mediated by the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR), with MR being involved in setting the HPA-axis activation threshold. Studies have revealed the importance of the MR in neuronal cells. However, little is known about its role in microglia which are thought to become maladaptive in AD. Thus, the project aims to 1) assess the impact of modulating MR activity on microglia function and 2) to evaluate effect of MR haplotypes that are known to alter MR activation. Human microglia cell-line (HMC3) were treated with MR agonist, Fludrocortisone, or MR antagonist, Spironolactone and cell survival, gene expression and inflammatory responses were assessed. These molecules modulated microglial MR activity and led to differential expression of several genes, including some related to stress responses, neuroinflammation, and AD. To confirm a major role for the MR in microglia function, current work is assessing the effects of combinations of MR and GR modulators and establishing HMC3 models of MR haplotypes prior to undertaking morphology, phagocytosis, migration, and cytokine production analyses. Overall, the findings from this study will provide novel insights into the role of the MR in microglial function and have implications in targeting this receptor in neurodegenerative diseases.