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

The inverse association between Alzheimer’s disease (AD) and cancer reported in epidemiological studies remains poorly understood. We injected melanoma B16F0 cells or saline into 5xFAD transgenic AD mice and wildtype (WT) controls and monitored tumor growth and cognitive performance (Y maze, Oasis maze) over 28 days. Melanoma- inoculated 5xFAD mice (5xFAD/B16F0) demonstrated improved cognition compared to 5xFAD/saline, regardless of tumor development, suggesting a systemic immune effect rather than one driven by 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, suggesting a shift toward a less reactive microglial phenotype. These results suggest that peripheral immune activation may modulate microglia in the hippocampus, offering preliminary insights into the biological basis of the AD and cancer inverse relationship.