Enhanced macrophage clearance of amyloid using nuclear receptor agonists
Case Western Reserve University School of Medicine
Supervising Advisor: Dr. Gary Landreth
Alzheimer ’s disease (AD) is characterized by the deposition and accumulation of amyloid (Aβ) plaques within the brain, which elicit a strong inflammatory response. Immune cells migrate toward Aβ plaques and attempt to clear them. However, the process of phagocytosis and clearance of Aβ plaques is inefficient. Previous studies have shown that nuclear receptor agonists improve the phagocytic process of myeloid cells, effectively increasing Aβ clearance in AD mice models with subsequent improvements in cognition. More recently, our lab has identified a mechanism by which nuclear receptors enhance phagocytosis in the AD brain via the activation of receptors MerTK and Axl. Additionally, there is new evidence that plaque associated macrophages originate from bone marrow derived monocytes which require the receptor TREM2 to infiltrate the brain. Further investigation into the roles of nuclear receptors, phagocytic machinery, and TREM2 in AD pathogenesis will help elucidate mechanisms by which to promote Aβ clearance.
This study is focused on the phagocytic receptors TREM2, MerTK and Axl on myeloid cells in the AD brain and their roles in inflammation and clearance of amyloid deposits.