Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China.
Guangdong Key Laboratory of Nanomedicine, CAS-HK Joint Lab for Biomaterials, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China.
Adv Sci (Weinh). 2024 Nov;11(42):e2405364. doi: 10.1002/advs.202405364. Epub 2024 Sep 3.
Astrocyte-microglia crosstalk is vital for neuronal survival and clearing aggregate accumulation in neurodegenerative diseases. While interleukin-3 (IL-3) has been reported to exert both protective and detrimental effects in neurodegenerative diseases, however, its role in α-synuclein pathology remains unclear. In this study, it is found that astrocytic IL-3 and microglial IL-3R are positively responsive to α-synuclein pathology in the brains of transgenic A53T Parkinson's disease (PD) mice and in an adeno-associated virus (AAV)-human α-synuclein (AAV-hα-Syn)-injected PD mouse model. Exogenous IL-3 infusion reduces behavioral abnormities and nigrostriatal α-synuclein pathology. Mechanistically, IL-3 induces microglial phagocytosis of pathological α-synuclein while simultaneously stimulating dopaminergic (DA) neurons to clear pathological α-synuclein via induction of autophagy through the IFN-β/Irgm1 pathway. Due to its limited efficiency in crossing the blood-brain barrier, a precise IL-3 delivery strategy is developed by cross-linking IL-3 and RVG29 with PEG-Linker (RVG-modified IL-3 nanogels-RVG-IL3 NGs). Intravenous administration of RVG-IL3 NGs shows efficient uptake by microglia and DA neurons within the brain. RVG-IL3 NGs ameliorate motor deficits and pathological α-synuclein by improving microglial and neuronal function in the AAV-hα-Syn mouse model of PD. Collectively, IL-3 may represent a feasible therapeutic strategy for PD.
星形胶质细胞-小胶质细胞相互作用对于神经元的存活和清除神经退行性疾病中的聚集物积累至关重要。虽然白细胞介素-3 (IL-3) 在神经退行性疾病中被报道具有保护和有害作用，但其在α-突触核蛋白病理中的作用仍不清楚。在这项研究中，发现星形胶质细胞的 IL-3 和小胶质细胞的 IL-3R 对转 A53T 帕金森病 (PD) 小鼠大脑中的α-突触核蛋白病理和腺相关病毒 (AAV)-人α-突触核蛋白 (AAV-hα-Syn) 注射 PD 小鼠模型中的α-突触核蛋白病理有正响应。外源性 IL-3 输注可减少行为异常和黑质纹状体α-突触核蛋白病理。从机制上讲，IL-3 通过 IFN-β/Irgm1 途径诱导自噬，从而诱导小胶质细胞吞噬病理性α-突触核蛋白，同时刺激多巴胺能 (DA) 神经元清除病理性α-突触核蛋白。由于其穿过血脑屏障的效率有限，因此通过将 IL-3 与 RVG29 用 PEG 接头 (RVG 修饰的 IL-3 纳米凝胶-RVG-IL3 NGs) 交联来开发精确的 IL-3 传递策略。RVG-IL3 NGs 的静脉内给药显示出通过改善 PD 的 AAV-hα-Syn 小鼠模型中的小胶质细胞和神经元功能，有效被大脑中的小胶质细胞和 DA 神经元摄取。RVG-IL3 NGs 通过改善小胶质细胞和神经元功能，改善运动缺陷和病理性α-突触核蛋白。总之，IL-3 可能代表 PD 的一种可行的治疗策略。
