Emerging roles for ITAM and ITIM receptor signaling in microglial biology and Alzheimer's disease-related amyloidosis

• Published in: Journal of neurochemistry Vol. 168; no. 10; pp. 3558 - 3573
• Main Authors: Samuels, Joshua D, Lukens, John R, Price, Richard J
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.10.2024
• Subjects: Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Amyloidosis; Amyloidosis - metabolism; Amyloidosis - pathology; Animals; Humans; Immune response; Immune system; Immunity, Innate; Immunoreceptor Tyrosine-Based Activation Motif; Immunoreceptor tyrosine-based inhibition motif; Innate immunity; Intracellular signalling; Microglia; Microglia - metabolism; Neurodegenerative diseases; Receptors; Receptors, Immunologic - metabolism; Senile plaques; Signal Transduction - physiology; Therapeutic targets; Tyrosine; β-Amyloid; innate immunity; ITAM; Alzheimer's disease; ITIM; microglia; amyloid beta
• ISSN: 0022-3042; 1471-4159; 1471-4159
• DOI: 10.1111/jnc.15981

Microglia are critical responders to amyloid beta (Aβ) plaques in Alzheimer's disease (AD). Therefore, the therapeutic targeting of microglia in AD is of high clinical interest. While previous investigation has focused on the innate immune receptors governing microglial functions in response to Aβ plaques, how microglial innate immune responses are regulated is not well understood. Interestingly, many of these microglial innate immune receptors contain unique cytoplasmic motifs, termed immunoreceptor tyrosine-based activating and inhibitory motifs (ITAM/ITIM), that are commonly known to regulate immune activation and inhibition in the periphery. In this review, we summarize the diverse functions employed by microglia in response to Aβ plaques and also discuss the innate immune receptors and intracellular signaling players that guide these functions. Specifically, we focus on the role of ITAM and ITIM signaling cascades in regulating microglia innate immune responses. A better understanding of how microglial innate immune responses are regulated in AD may provide novel therapeutic avenues to tune the microglial innate immune response in AD pathology.