Many of the human genes associated with increased risk for Alzheimer’s disease (AD) are exclusively expressed in the brain by microglia. Microglia express the tumor-associated macrophage (TAM) receptor tyrosine kinases Axl and Mer, which have been linked to AD. Huang et al. performed molecular, genetic, cell biological, and in vivo two-photon imaging analyses of AD mouse models crossed into Axl- and Mertk-knockout mouse mutants. Induced expression of Axl and Mer in plaque-associated microglia led to the recruitment of the TAM ligand Gas6 and to the formation of dense accumulations of phagocytosed amyloid within the microglia. An AD mouse model lacking Axl and Mer did not phagocytose amyloid as normal. Despite this, the mice developed fewer plaques than AD mice with normal microglia. Thus, TAM receptor signaling is required for microglial recognition of amyloid plaques, and, counterintuitively, TAM-driven microglial phagocytosis promotes plaque deposition and growth.
Nat. Immunol. 22, 586 (2021).