Attenuation of Tau Hyperphosphorylation by Chronic Toxoplasma gondii Infection in a Mouse Model of Alzheimer's Disease

ABSTRACT

Alzheimer's disease (AD) is characterized by amyloid‐β (Aβ) peptide accumulation and tau protein‐mediated neurodegeneration, and neuroinflammation is increasingly recognized as a major process associated with tau pathology. Chronic Toxoplasma gondii infection reduces amyloid accumulation in AD models through immune modulation, but its stage‐specific associations with tau‐related pathology remain unclear. Here, we investigated how chronic T . gondii infection is associated with tau‐related molecular and neuropathological changes in the 5XFAD AD mouse model. At 40 weeks post‐infection, we profiled transcriptomic changes and evaluated Aβ‐associated (21 genes), Aβ/tau‐shared (22 genes), and tau‐associated (21 genes) pathological programs together with p‐tau immunoreactivity in brain sections. Chronic infection was associated with selective modulation of molecular networks linked to neuroimmune signalling and tau‐related pathways rather than broad suppression of AD‐related gene expression. Among tau‐related pathological stages, the neuroinflammation‐related amplification module linking Aβ and tau exhibited the most prominent transcriptomic change in T. gondii‐ infected AD mice, whereas upstream kinase‐related initiation pathways and downstream toxin conversion or accumulation‐related processes changed relatively minimally. These transcriptomic changes were accompanied by a marked reduction in phosphorylated tau load at the tissue level. Collectively, these findings suggest that chronic T. gondii infection is associated with selective modulation of tau‐related pathogenic programs and reduced p‐tau burden in the 5XFAD brain.