Melanoma cell inoculation improves cognitive impairment in the 5xFAD mouse model of Alzheimer's disease.

UNLABELLED: The inverse association between Alzheimer’s disease (AD) and cancer reported in epidemiological studies remains poorly understood. Five-month-old female and male 5xFAD transgenic AD mice and wildtype (WT) littermate controls were injected with melanoma B16F0 cells or solvent and subsequently monitored for tumor growth and cognitive performance using the Y and Oasis maze for 28 days. Melanoma-inoculated 5xFAD mice (5xFAD/B16F0) demonstrated improved cognition compared to 5xFAD/saline, regardless of tumor development, suggesting a possible contribution of systemic immune modulation rather than a direct effect of tumor growth. 5xFAD/B16F0 mice also showed reduced tumor incidence than WT mice, as well as an increased number of splenic myeloid cells. Although amyloid-β levels and the number of astrocytes and microglia were unchanged, microglial soma area in the hippocampus was reduced in 5xFAD/B16F0 mice, suggesting a shift toward a less reactive microglial morphology. Collectively, these results suggest that peripheral immune changes associated with melanoma inoculation may influence microglial morphology, providing preliminary insights into the potential mechanisms underlying the inverse relationship between AD and cancer. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-026-40699-w.