Many neurodegenerative risk genes are predominantly expressed in microglia, the primary immune cells in the central nervous system. Our lab has demonstrated that two microglial TAM receptor tyrosine kinases - Axl and Mer – control multiple features of microglia physiology. Importantly, recent transcriptomic analysis has linked TAM receptors to Alzheimer’s disease (AD) and Amyotrophic lateral sclerosis (ALS). This thesis dissertation describes original work that examines the expression and function of TAM receptors and their ligands in AD and ALS. We find that in AD and its mouse models, induced expression of Axl and Mer in amyloid plaque-associated microglia is coupled to induced plaque decoration by the TAM ligand Gas6 and its co-ligand phosphatidylserine. Prior to plaque deposition in the APP/PS1 AD model, genetic ablation of Mer alone leads to a marked increase incidence of lethal epileptic seizures. After deposition of plaques, ablation of Axl and Mer results in microglia that are unable to normally detect, respond to, organize, or phagocytose amyloid beta plaques, a hallmark of AD pathology. These major deficits notwithstanding, TAM-deficient AD mice develop fewer dense-core plaques than AD mice. Our findings reveal that the TAM system is an essential mediator of microglial recognition and engulfment of plaques, and that TAM-driven microglial phagocytosis does not constrain, but rather promotes, plaque development. In an ALS model, we find that TAM system is similarly strongly activated in microglia during disease progression. ALS mice in the absence of Axl and Mer have significantly advanced symptom onset, but their disease course is almost twice as long as that of TAM-expressing ALS mice. This delayed arrival of the end stage of disease may be accompanied by dampened inflammation and an increased survival of ALS-vulnerable motor neurons as a result of TAM deficiency. Original work in this dissertation suggests a critical and differential involvement of TAM receptors in early and late stages of both AD and ALS. With several whole-body TAM receptor antagonists already in development and clinical trials as cancer therapeutics, a thorough understanding of the roles of microglial TAM receptors in neurodegeneration is of genuine importance to public health.

Little is understood about the genesis of autoimmune diseases caused by deficiencies in TAM receptors (Tyro3, Axl, Mer). One of the causes of autoimmunity could be defective thymic education. Our goal was to elucidate the localization and role of TAM receptors and their ligands within the thymus. We show that Axl and Mer, but not Tyro3, are expressed within the thymus. Through immunohistochemistry, we identify Axl and Mer expression primarily on macrophages in both the medulla and cortex. Using knockout mice, we show that Axl and Mer perform necessary but redundant roles in the elimination of basally accumulated apoptotic thymocytes. The absence of both receptors leads to immense apoptotic cell accumulation within thymic cortex and medulla.These changes result in minor morphological defects as the weight but not the ratio of medulla to cortex was affected in the Axl-/-Mertk-/- mice. We further use this model to instigate Axl dependence on Gas6 as a ligand in thymus. Additionally, we show that during acute thymocyte apoptosis, Mer but not Axl is critical in cellular clearance.