Friday, April 26, 2024
4/26/2024
ABSTRACT The C-type lectin receptor CLEC7A has recently been identified to be one of the most highly upregulated molecules expressed by microglia in various neurodegenerative disorders, including Alzheimer’s disease. Yet, little is currently known about the role of CLEC7A in neurodegenerative disease pathogenesis. CLEC7A is best known for its critical involvement in the mounting of protective immunity to fungal infections. CLEC7A aids in the elimination of fungal pathogens by promoting the induction of phagocytosis as well as coordinating the production of proinflammatory cytokines and reactive oxygen species. More recent studies have also shown that CLEC7A can respond to self-derived molecules such as annexins expressed by dead cells. However, in contrast to the pro-inflammatory effector responses generated following CLEC7A detection of fungi, engagement of CLEC7A by endogenously-derived molecules has largely been shown to trigger anti-inflammatory and tolerogenic immune responses. In our preliminary studies, we found that deletion of CLEC7A in the 5xFAD mouse model of Alzheimer’s disease leads to increased mobilization of microglia to amyloid beta (A¿) plaques, decreased levels of A¿ deposition, and improved neuronal health. In contrast, we find that inducing overt activation of CLEC7A signaling via hippocampal injection of a fungal-derived CLEC7A agonist boosts A¿ clearance and microglial activation in 5xFAD mice. Given these collective findings, we hypothesize that the effects of CLEC7A on microglial function and A¿ control are ligand-specific, where endogenously-derived CLEC7A activators generated in A¿ amyloidosis can suppress beneficial microglial responses and fungal-derived CLEC7A agonists can conversely promote microglial activation and A¿ clearance. To test this working hypothesis, we will first thoroughly define how germline ablation of CLEC7A affects Alzheimer’s-related disease progression in the 5xFAD mouse model (Aim 1). We have recently generated novel Clec7a conditional knockout mice (Clec7afl/fl mice) and we will leverage this new genetic tool in Aim 2 to interrogate a microglia-specific role for CLEC7A in controlling A¿ amyloidosis, neuroinflammation, and brain pathology in 5xFAD mice. In our third Aim, we will investigate the effects that various endogenous, therapeutic, and pathogen-derived CLEC7A agonists have on microglial responses in multiple Alzheimer’s disease-related in vivo mouse models as well as in human microglia- like cells generated from induced pluripotent stem cells.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
