Systemic inflammation activates coagulation and immune cell infiltration pathways in brains with propagating α-synuclein fibril aggregates.
Mol Cell Neurosci
; 129: 103931, 2024 Jun.
Article
em En
| MEDLINE
| ID: mdl-38508542
ABSTRACT
Synucleinopathies are a group of diseases characterized by brain aggregates of α-synuclein (α-syn). The gradual accumulation of α-syn and the role of inflammation in early-stage pathogenesis remain poorly understood. We explored this interaction by inducing chronic inflammation in a common pre-clinical synucleinopathy mouse model. Three weeks post unilateral intra-striatal injections of human α-syn pre-formed fibrils (PFF), mice underwent repeated intraperitoneal injections of 1 mg/ml lipopolysaccharide (LPS) for 3 weeks. Histological examinations of the ipsilateral site showed phospho-α-syn regional spread and LPS-induced neutrophil recruitment to the brain vasculature. Biochemical assessment of the contralateral site confirmed spreading of α-syn aggregation to frontal cortex and a rise in intracerebral TNF-α, IL-1ß, IL-10 and KC/GRO cytokines levels due to LPS. No LPS-induced exacerbation of α-syn pathology load was observed at this stage. Proteomic analysis was performed contralateral to the PFF injection site using LC-MS/MS. Subsequent downstream Reactome Gene-Set Analysis indicated that α-syn pathology alters mitochondrial metabolism and synaptic signaling. Chronic LPS-induced inflammation further lead to an overrepresentation of pathways related to fibrin clotting as well as integrin and B cell receptor signaling. Western blotting confirmed a PFF-induced increase in fibrinogen brain levels and a PFF + LPS increase in Iba1 levels, indicating activated microglia. Splenocyte profiling revealed changes in T and B cells, monocytes, and neutrophils populations due to LPS treatment in PFF injected animals. In summary, early α-syn pathology impacts energy homeostasis pathways, synaptic signaling and brain fibrinogen levels. Concurrent mild systemic inflammation may prime brain immune pathways in interaction with peripheral immunity.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Encéfalo
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Lipopolissacarídeos
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Alfa-Sinucleína
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Inflamação
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Mol Cell Neurosci
Assunto da revista:
BIOLOGIA MOLECULAR
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NEUROLOGIA
Ano de publicação:
2024
Tipo de documento:
Article