Microglial Junb deletion exacerbate amyloid plaque load in Alzheimer’s disease mice model

Alzheimer’s disease (AD) is a late-onset, neurodegenerative disease. Two hallmark findings of AD include the presence of extracellular deposition of Amyloid Beta (Aβ)/senile plaques and intracellular accumulation of neurofibrillary tangles (NFT) in the neuronal cells. Aberrant deposition of amyloid beta (Aß) contributes to neuroinflammation and AD progression. Microglia, the resident immune cells in the brain, detect Aß and initiate the process of Aß phagocytosis and clearance inhibiting plaque accumulation. During aging, these microglia become dysfunctional leading to the irreversible loss of neurons in the hippocampus and cognitive deficits. Therefore, identifying signaling molecules regulating microglial functions aimed at Aβ clearance offers a potential target in developing new treatments for AD. By conducting Single Cell RNA sequencing on microglia derived from the AD mice model, we identified a subset of microglia, DAM-1, which was highly effective in removing plaques. These DAM-1, were characterized by elevated levels of AP-1 transcriptional factor machinery including Junb and Fos. In the present study, we hypothesize that Junb plays a major role in regulating microglial phagocytic function. Using primary microglia culture derived from WT and microglial-specific Junb deficient mice, we demonstrated that Junb regulates microglia-mediated clearance of Aβ (1-42) by modulating phagocytic activity. Our preliminary results indicate that pretreatment with pharmacological inhibitors of Junb (T-5224) significantly reduced the uptake of pH Rodo E. coli bioparticles as well as HiLyte™ Fluor labeled β-Amyloid (1-42) in microglia. To validate the function of Junb in the invivo Alzheimer’s disease mice model (5xFAD), we developed a transgenic mouse model in which, post tamoxifen injection, we can selectively delete Junb expression in the microglia. Post deletion confirmation, Junb fl/fl were crossed with 5xFAD mice to induce amyloid pathology. Two months post injection, we compared plaque load in AD mice with and without Junb deletion with WT 5xFAD mice. We observed a significant increase in plaque load in Junb deficient 5xFAD mice, suggesting a critical role of Junb in regulating Aβ phagocytosis. Currently, our research focuses on identifying downstream signaling pathways/genes regulated by AP-1 transcriptional machinery, which might serve as a novel strategy for the treatment of Alzheimer’s disease.