TNF-related hippocampal inflammatory remodeling links synaptic injury and hippocampus-dependent behavioral deficits following Angiostrongylus cantonensis infection

Angiostrongylus cantonensis is a neurotropic parasite and a leading cause of eosinophilic meningitis worldwide. In non-permissive hosts, invading larvae enter the central nervous system but fail to complete development and degenerate within neural tissue, creating a distinctive form of parasite-driven neuroinflammation. Although cognitive impairment and persistent neurological sequelae have been reported in neuroangiostrongyliasis, it remains unclear how this unusual host–parasite interaction precipitates hippocampal circuit injury, synaptic pathology and cognitive decline. Here, we investigated hippocampal injury in a mouse model of A. cantonensis infection and defined the inflammatory programs associated with synaptic dysfunction. BALB/c mice were inoculated with infective third-stage larvae of A. cantonensis . Hippocampus-dependent spatial cognitive performance was evaluated using the Morris water maze and Y-maze behavioral assays. Neuropathological and synaptic alterations were assessed by magnetic resonance imaging, transmission electron microscopy, western blotting, Nissl staining and immunofluorescence. RNA-seq was conducted for hippocampal transcriptional profiling, followed by differentially expressed genes (DEGs) screening, gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), gene set enrichment (GSEA) and protein–protein interaction (PPI) network analyses. Single-cell phenotype association analysis (scPAS) was implemented to dissect cell-type-specific transcriptional perturbations. Multi-layer behavioral, histological and molecular readouts were collected to characterize the combinatorial therapeutic efficacy of albendazole plus thalidomide. A. cantonensis infection was associated with brain injury, hippocampus-linked behavioral deficits, and progressive hippocampal synaptic abnormalities. Transcriptomic profiling revealed enrichment of cytokine- and complement-associated pathways, alongside suppression of neuronal and synaptic programs. PPI network analysis pinpointed Tnf as a core hub gene. scPAS analysis suggested that the bulk hippocampal transcriptional changes corresponded to neuronal and astrocyte-related cell-type signatures, while histological analyses showed hippocampal injury and glial inflammatory changes. Albendazole plus thalidomide attenuated Tnf/Tnfr1/C3-related inflammatory alterations and component 3 (C3) accumulation in microglia-associated regions. These pathological improvements were accompanied by partial restoration of synaptic integrity and behavioral performance. These findings identify coordinated tumor necrosis factor (TNF)-related inflammation, complement-associated glial remodeling and synaptic degeneration as key features of hippocampal pathology in neuroangiostrongyliasis. The study expands the pathological framework of A. cantonensis infection beyond acute eosinophilic meningitis to encompass inflammatory remodeling of hippocampal circuits, and highlights host-directed immunomodulation as a promising therapeutic strategy for mitigating parasite-associated neurological injury.