biostudies-literatureMcAlpine CSNHLBI NIH HHSNCI NIH HHSNIGMS NIH HHS701-706https://www.ebi.ac.uk/biostudies/studies/S-EPMC8934148biostudies-literatureUnknown595(7869)Communication within the glial cell ecosystem is essential for neuronal and brain health^1-3. The influence of glial cells on the accumulation and clearance of β-amyloid (Aβ) and neurofibrillary tau in the brains of individuals with Alzheimer's disease (AD) is poorly understood, despite growing awareness that these are therapeutically important interactions^4,5. Here we show, in humans and mice, that astrocyte-sourced interleukin-3 (IL-3) programs microglia to ameliorate the pathology of AD. Upon recognition of Aβ deposits, microglia increase their expression of IL-3Rα-the specific receptor for IL-3 (also known as CD123)-making them responsive to IL-3. Astrocytes constitutively produce IL-3, which elicits transcriptional, morphological, and functional programming of microglia to endow them with an acute immune response program, enhanced motility, and the capacity to cluster and clear aggregates of Aβ and tau. These changes restrict AD pathology and cognitive decline. Our findings identify IL-3 as a key mediator of astrocyte-microglia cross-talk and a node for therapeutic intervention in AD.NatureAstrocytic interleukin-3 programs microglia and limits Alzheimer's disease.PMC8934148R35 HL139598K99 HL151750P01 HL142494R01 HL158534R01 CA158534R00 CA218870P01 HL131478F31 HL147364R35 GM139598R35 HL135752R00 HL151750R13 CA135752Kahles FFeruglio PFKim ESadreyev RIChristie KAMindur JEKleinstiver BPMcAlpine CSGriciuc ADowney JPoller WCIwamoto YAnzai ATanzi RESingh SChan CTJanssen HNahrendorf MPark JWeissleder RJorfi MHe SChoi SHSwirski FKKiss MGWong LPVinegoni CfalseAstrocytic interleukin-3 programs microglia and limits Alzheimer's disease.Communication within the glial cell ecosystem is essential for neuronal and brain health^1-3. The influence of glial cells on the accumulation and clearance of β-amyloid (Aβ) and neurofibrillary tau in the brains of individuals with Alzheimer's disease (AD) is poorly understood, despite growing awareness that these are therapeutically important interactions^4,5. Here we show, in humans and mice, that astrocyte-sourced interleukin-3 (IL-3) programs microglia to ameliorate the pathology of AD. Upon recognition of Aβ deposits, microglia increase their expression of IL-3Rα-the specific receptor for IL-3 (also known as CD123)-making them responsive to IL-3. Astrocytes constitutively produce IL-3, which elicits transcriptional, morphological, and functional programming of microglia to endow them with an acute immune response program, enhanced motility, and the capacity to cluster and clear aggregates of Aβ and tau. These changes restrict AD pathology and cognitive decline. Our findings identify IL-3 as a key mediator of astrocyte-microglia cross-talk and a node for therapeutic intervention in AD.2021-01-01T00:00:00Z2021 Jul2026-05-31T22:48:18.596Z2025-04-04T19:29:59.912ZS-EPMC89341483426217810.1038/s41586-021-03734-6