Communication within the glial cell ecosystem is essential for neuronal and brain health^1,2,3. 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.

神经胶质细胞生态系统内的通信对于神经元和大脑健康^1,2,3至关重要。神经胶质细胞对阿尔茨海默病 (AD) 患者大脑中 β-淀粉样蛋白 (Aβ) 和神经原纤维 tau 的积累和清除的影响知之甚少，尽管人们越来越意识到这些是治疗上重要的相互作用^4,5. 在这里，我们在人类和小鼠中展示了星形胶质细胞来源的白细胞介素 3 (IL-3) 对小胶质细胞进行编程以改善 AD 的病理。在识别 Aβ 沉积物后，小胶质细胞会增加其 IL-3Rα（IL-3 的特异性受体（也称为 CD123））的表达，从而使它们对 IL-3 产生反应。星形胶质细胞组成性地产生 IL-3，它引发小胶质细胞的转录、形态和功能编程，赋予它们急性免疫反应程序、增强的运动性以及聚集和清除 Aβ 和 tau 聚集体的能力。这些变化限制了 AD 病理学和认知能力下降。我们的研究结果将 IL-3 确定为星形胶质细胞-小胶质细胞串扰的关键介质和 AD 治疗干预的节点。