Systemic inflammation activates coagulation and immune cell infiltration pathways in brains with propagating α-synuclein fibril aggregates

• DOI: 10.1016/j.mcn.2024.103931
• Publication Date: 2024-03-19T02:50:11Z
• Authors: Anne-Line Strange...; Mikkel Vestergaar...; Jonas Folke; Tomasz Brudek; Luisa Harriet Knecht; Florence Sotty; Kate Lykke Lamber...; Karina Fog; Louise Torp Dalgaard; Susana Aznar
• Keywords: Gliosis; Pathogenesis

Synucleinopathies are a group of diseases characterized by brain aggregates α-synuclein (α-syn). The gradual accumulation α-syn and the role inflammation in early-stage pathogenesis remain poorly understood. We explored this interaction inducing chronic common pre-clinical synucleinopathy mouse model. Three weeks post unilateral intra-striatal injections human pre-formed fibrils (PFF), mice underwent repeated intraperitoneal 1 mg/ml lipopolysaccharide (LPS) for 3 weeks. Histological examinations ipsilateral site showed phospho-α-syn regional spread LPS-induced neutrophil recruitment to vasculature. Biochemical assessment contralateral confirmed spreading aggregation frontal cortex rise intracerebral TNF-α, IL-1β, IL-10 KC/GRO cytokines levels due LPS. No exacerbation pathology load was observed at stage. Proteomic analysis performed PFF injection using LC-MS/MS. Subsequent downstream Reactome Gene-Set Analysis indicated that alters mitochondrial metabolism synaptic signaling. Chronic further lead an overrepresentation pathways related fibrin clotting as well integrin B cell receptor Western blotting PFF-induced increase fibrinogen + LPS Iba1 levels, indicating activated microglia. Splenocyte profiling revealed changes T cells, monocytes, neutrophils populations treatment injected animals. In summary, early impacts energy homeostasis pathways, signaling levels. Concurrent mild systemic may prime immune with peripheral immunity.