Nanotherapeutic Approaches of Interleukin‐3 to Clear the α‐Synuclein Pathology in Mouse Models of Parkinson's Disease

Abstract

AbstractAstrocyte‐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.