Cobrotoxin mitigates neuroinflammation and cognitive impairment by suppressing CD8+ T cell-microglia interactions in male 5 × FAD mice.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline accompanied by chronic neuroinflammation. Emerging evidence implicates T-cell infiltration and microglial activation as key immune events that accelerate AD pathology, yet therapeutic approaches targeting this neuroimmune interface remain scarce. Cobrotoxin (CTX), a short-chain neurotoxin derived from Naja atra venom, exhibits potent anti-inflammatory and immunomodulatory properties and is clinically approved in China for the treatment of chronic pain syndromes. Here, we investigated whether CTX could alleviate neuroinflammation and cognitive deficits in 5 × FAD mice, a transgenic model of AD. Intranasal CTX administration for nine weeks enhanced spatial learning and memory in the Morris water maze without altering amyloid-β burden. Flow cytometry and immunofluorescence revealed that CTX markedly reduced brain-infiltrating CD8+ T cells and downregulated chemokines implicated in T cell-microglia communication, including Cxcl9, Cxcl10, Cxcl16, and Ccl5. Consistent with this, CTX attenuated microglial activation and pro-inflammatory cytokine release while preserving plaque-associated microglia (disease-associated microglia, DAM). Morphological and electrophysiological analyses demonstrated that CTX restored dendritic complexity, spine density, and hippocampal long-term potentiation (LTP), indicating improved synaptic integrity. Collectively, these findings identify CTX as a potent modulator of neuroimmune signaling that mitigates neuroinflammation and synaptic dysfunction in AD, suggesting its potential for repurposing as an immunomodulatory therapy for neurodegenerative diseases.