Astrocyte-derived interleukin-3 reprograms microglia and limits Alzheimer’s disease

Communication within the glial cell ecosystem is essential to neuronal and brain health 1 – 3 . In Alzheimer’s disease, progressive neurodegeneration is characterized by β-amyloid (Aβ) deposition and neurofibrillary tau formation. The influence of glial cells on Aβ and tau accumulation and clearance is poorly understood, despite growing awareness that these are important interactions with potential for therapeutic intervention 4 , 5 . Here we show, in mice and humans, that astrocyte-sourced interleukin-3 (IL-3) reprograms microglia to ameliorate Alzheimer’s disease pathology. Upon recognition of Aβ deposits, microglia augment IL-3Rɑ, IL-3’s specific receptor, rendering them responsive to IL-3. Astrocytes constitutively produce IL-3, which elicits transcriptional, morphological, and functional reprograming of microglia endowing them with an acute immune response program, enhanced motility, and the capacity to cluster and clear Aβ and tau aggregates. These changes restrict Alzheimer’s disease pathology and cognitive decline. This study identifies IL-3 as a critical mediator of astrocyte-microglia crosstalk and a node for therapeutic intervention in Alzheimer’s disease.