Abstract Body

Two microglial TAM receptor tyrosine kinases - Axl and Mer - have been linked to Alzheimer’s disease, but their roles in disease have not been tested experimentally. We find that in Alzheimer’s disease 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. In the APP/PS1 mouse model of Alzheimer’s disease, we show that genetic ablation of Axl and Mer results in microglia that are unable to normally detect, respond to, organize, or phagocytose amyloid beta plaques. These major deficits notwithstanding, and contrary to expectation, TAM-deficient APP/PS1 mice develop fewer dense-core plaques than APP/PS1 mice with normal microglia. Our findings reveal that the TAM system is an essential mediator of microglial recognition and engulfment of amyloid plaques, and that TAM-driven microglial phagocytosis does not inhibit, but rather promotes, dense-core plaque development. Thus, dense-core plaques do not form spontaneously, but are instead constructed via microglial phagocytosis, and much of this phagocytosis is mediated by Mer and Axl. With regard to their construction by microglia, dense-core plaques may be viewed as macrophage-generated granulomas. As such, their simple dis-aggregation by drugs such as aducanumab may be contraindicated as an Alzheimer's disease therapy.