Context-Dependent Regulation of Microglial Metabolic and Immune States via IL-3/CD123 Signaling: Implications for Glial Crosstalk and Cognitive Impairment.

Cognitive impairment (CI), spanning mild memory issues to severe dementia, impacts over 55 million people worldwide and have a significant effect that strains health, economy, and caregiving. Surprisingly, it occurs at any age. The glial cell ecosystem, particularly astrocyte-microglia crosstalk, is pivotal for brain homeostasis and cognitive function across the lifespan. Intriguingly, in recent discoveries, dysregulation of ecosystem contributes to neurodevelopmental disorders (NDDs), adult cognitive decline, and neurodegenerative diseases like Alzheimer's disease (AD), and astrocyte-derived interleukin-3 (IL-3), acting via the IL-3/CD123-related signals, may act as a key regulatory mediator of microglial function. Over the past few decades, extensive researches have been devoted to investigating aging-related regulatory factors with the aim of deciphering the "code" underlying cognitive developmental abnormalities, premature cognitive decline, and neurodegeneration. Astrocyte-microglia crosstalk governs age-dependent glial turnover via senescence-sensitive IL-3. Under pathological conditions, perturbed turnover's association with age-stratified CI and its regulators is poorly understood. This review integrates current evidence on glial crosstalk, cellular senescence, and repopulation to elucidate age-specific CI driven by dysregulated glial turnover, while identifying key biomarkers that can predict aging processes. Looking ahead, therapeutic strategies targeting the IL-3/CD123-related signals regulating glial crosstalk hold promise for advancing interventions in immune-mediated CI across the lifespan.