Tetanus toxoid immunoprophylaxis boosts cognitive function by promoting hippocampal neurogenesis and white matter myelination in ageing experimental mice.

Tetanus toxoid (TT), a widely administered prophylactic immunogen, not only provides protection against tetanus but also exerts neuromodulatory effects, for which experimental evidence remains limited. In this study, we investigated the effect of TT on cognitive function in relation to hippocampal neurogenesis, myelination, key markers for neuroinflammation, oxidative stress and cell death in the brain of twelve-month-old mice. The treatment group exhibited higher levels of immunoglobulin gamma (IgG) and increased lymphocyte count in the blood sample. Results from the novel object recognition (NOR) test, cued radial arm maze (cued RAM), and Morris water maze (MWM) revealed that TT administration enhanced learning and memory in ageing mice. These cognitive improvements were associated with an increased number of doublecortin (DCX)-positive immature neurons and a higher proportion of bromodeoxyuridine (BrdU)/neuronal nuclei (NeuN) double-positive new neurons in the hippocampus. In addition, TT treatment resulted in enhanced myelination in the corpus callosum, hippocampal hilus and striatum as evidenced by increased intensity of luxol fast blue (LFB) staining and myelin basic protein (MBP) expression. Moreover, TT treatment induced a phenotypic shift in microglial phenotype from the pro-inflammatory M1 state to the neuroprotective M2 state. TT-treated animals showed a significant reduction in the levels of an oxidative stress marker, malondialdehyde (MDA), and a lower number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) cells, suggesting that TT alleviates oxidative stress and prevents neuronal apoptosis. Overall, these findings demonstrate TT as a potential modulator of neuroregeneration, remyelination and neuroprotection, emphasizing its therapeutic potential for enhancing cognitive function.