Center for Systems Biology and Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Cardiovascular Research Institute and Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Nature. 2021 Jul;595(7869):701-706. doi: 10.1038/s41586-021-03734-6. Epub 2021 Jul 14.
Communication within the glial cell ecosystem is essential for neuronal and brain health. 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. 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讯对于神经元和大脑健康至关重要。尽管人们越来越意识到这些相互作用具有重要的治疗意义，但胶质细胞对阿尔茨海默病（AD）患者大脑中β-淀粉样蛋白（Aβ）和神经纤维缠结的积累和清除的影响仍知之甚少。在这里，我们在人类和小鼠中表明，星形胶质细胞来源的白细胞介素 3（IL-3）可使小胶质细胞发生程序改变，从而改善 AD 的病理。当小胶质细胞识别到 Aβ 沉积时，会增加白细胞介素 3 受体α（IL-3Rα）的表达——这是 IL-3 的特异性受体（也称为 CD123），从而使它们对 IL-3 产生反应。星形胶质细胞持续产生 IL-3，这会引发小胶质细胞的转录、形态和功能编程，使它们具有急性免疫反应程序、增强的迁移能力以及聚集和清除 Aβ 和 tau 聚集体的能力。这些变化限制了 AD 的病理和认知能力下降。我们的研究结果表明，IL-3 是星形胶质细胞-小胶质细胞相互作用的关键介质，也是 AD 治疗干预的一个节点。
