摘要 : Regional iron accumulation and a-synuclein (a-syn) spreading pathology within the central nervous system are common pathological findings in Parkinson's disease (PD). Whereas iron is known to bind to a-syn, facilitating its aggreg... 展开 Regional iron accumulation and a-synuclein (a-syn) spreading pathology within the central nervous system are common pathological findings in Parkinson's disease (PD). Whereas iron is known to bind to a-syn, facilitating its aggregation and regulating a-syn expression, it remains unclear if and how iron also modulates a-syn spreading. To elucidate the influence of iron on the propagation of a-syn pathology, we investigated a-syn spreading after stereotactic injection of a-syn preformed fibrils (PFFs) into the striatum of mouse brains after neonatal brain iron enrichment. C57Bl/6J mouse pups received oral gavage with 60, 120, or 240 mg/kg carbonyl iron or vehicle between postnatal days 10 and 17. At 12 weeks of age, intrastriatal injections of 5-\ig PFFs were performed to induce seeding of a-syn aggregates. At 90 days post-injection, PFFs-injected mice displayed long-term memory deficits, without affection of motor behavior. Interestingly, quantification of a-syn phosphorylated at S129 showed reduced alpha-syn pathology and attenuated spreading to connectome-specific brain regions after brain iron enrichment. Furthermore, PFFs injection caused intrastriatal microglia accumulation, which was alleviated by iron in a dose-dependent way. In primary cortical neurons in a microfluidic chamber model in vitro, iron application did not alter trans-synaptic a-syn propagation, possibly indicating an involvement of non-neuronal cells in this process. Our study suggests that a-syn PFFs may induce cognitive deficits in mice independent of iron. However, a redistribution of a-syn aggregate pathology and reduction of striatal microglia accumulation in the mouse brain may be mediated via iron-induced alterations of the brain connectome. 收起