Microglial ITAM & ITIM Signaling in Neurodegenerative Disease and Brain Aging

Innate immunity within the central nervous system (CNS) plays key roles in shaping both healthy brain aging and vulnerability to neurodegenerative disease. Microglia, the tissue-resident macrophages of the CNS, play a key role in mediating the innate immune responses to age-associated pathologies. A growing body of literature details the roles of microglia in responding to white matter degeneration, misfolded proteins, and cell death. These functions depend on cell-surface receptors that enable microglia to sample and react to changes in their environment. Recent studies highlight the importance of receptors associated with immunoreceptor tyrosine-based activation and inhibitory motifs (ITAMs/ITIMs) in pathological brain aging. In this review, we describe how ITAM/ITIM-associated receptors and their downstream signaling pathways shape microglial responses to neurodegenerative disease and aging. A deeper understanding of microglial activation and resolution may provide tools to harness these cells' capacity to maintain and extend neurological healthspan.