Molecular and cognitive signatures of ageing partially restored through synthetic delivery of IL2 to the brain. Molecular and cognitive signatures of ageing partially restored through synthetic delivery of IL2 to the brain

Cognitive decline is a common pathological outcome during aging, with an ill-defined cellular or molecular basis. Among the cellular changes observed with age are alterations to neuronal plasticity, changes in the glial compartment and the decline of the neurogenic niche. In the recent years, the concept of inflammaging, defined as a low-grade inflammation increasing with age, has emerged as a nexus for age-related diseases. This increase of basal inflammation is also observed in the central nervous system. While not classically considered a neurological cell type, infiltrating T cells increase in the brain with age, and may be responsible for amplification of inflammatory cascades and disruptions to the neurogenic niche. Recently, a small resident population of regulatory T cells has been identified in the brain, and the capacity of IL2-mediated expansion of this population to counter neuroinflammatory disease has been demonstrated. Here we test a brain-specific IL2 delivery system for the prevention of neurological decline in aging mice. We identify the molecular hallmarks of aging in the brain glial compartments, and identify partial restoration of this signature through IL2 treatment. At a behavioral level, brain IL2 delivery prevented the age-induced defect in learned memory formation during maze tests, without improving the general decline in motor skill or novelty-seeking behavior. These results identify immune modulation as a potential path to preserving cognitive function for healthy ageing. Overall design: C57BL/6 mice were treated at ages 2 months and 22 months with either control vector PHP.GFAP-GFP or the treatment vector PHP.GFAP-IL2. Two months later, astrocytes, microglia, oligodendrocytes and oligodendrocyte precursors were sort-purified from the mouse brains for 10x single cell transcriptomics analysis.

认知衰退是衰老过程中常见的病理结局，但其细胞及分子基础尚不明确。衰老过程中观察到的细胞变化包括神经元可塑性改变、胶质区室（glial compartment）异常及神经源性微环境（neurogenic niche）功能衰退。近年来，以“随年龄增长而升高的低度炎症”定义的炎性衰老（inflammaging）概念，已成为衰老相关疾病的关键关联枢纽。中枢神经系统中同样存在这种基础炎症水平升高的现象。尽管浸润性T细胞通常不被归类为神经细胞，但随年龄增长其在脑中的丰度会增加，可能参与放大炎症级联反应并破坏神经源性微环境。近期研究在脑中发现了少量驻留性调节性T细胞（regulatory T cells），且已有研究证实白细胞介素2（IL2）介导的该细胞群扩增可对抗神经炎症性疾病。本研究针对衰老小鼠，评估了脑特异性IL2递送系统对神经衰退的预防作用。我们鉴定了脑胶质区室衰老的分子特征谱，并证实IL2治疗可部分逆转该特征。行为学层面，脑靶向IL2递送可阻断迷宫实验中年龄诱导的习得性记忆形成缺陷，但未改善运动技能或探索新奇行为的整体衰退。上述结果表明，免疫调控或可成为实现健康衰老、维持认知功能的潜在途径。实验整体设计：将2月龄和22月龄的C57BL/6小鼠分别注射对照载体PHP.GFAP-GFP或治疗载体PHP.GFAP-IL2。两个月后，从小鼠脑中分选纯化星形胶质细胞、小胶质细胞、少突胶质细胞及少突胶质前体细胞，用于10x单细胞转录组测序分析。