Acute viral encephalitis impacts dense‐core amyloid plaque pathology and dysregulates myeloid responses to amyloid plaques

INTRODUCTION Recent epidemiological datasets have associated viral encephalitis exposure (i.e., viral‐induced neuroinflammation) with increased risk of Alzheimer's disease (AD) and dementia, highlighting the need to uncover how it may impact AD neuropathology. METHODS Aged 5xFAD and wild‐type (WT) mice were infected with the John Howard Mueller strain of murine hepatitis virus (JHMV), a neurotropic strain of murine coronavirus to comprehensively determine how coronavirus‐induced encephalitis may induce molecular and cellular changes that impact beta‐amyloid (Aβ) neuropathology. RESULTS JHMV‐induced encephalitis at 12 days post‐infection resulted in minimal changes to overall Aβ protein, despite increased CD4 + and CD8 + T‐cell infiltration and Lgals3/ MAC2‐expressing macrophages surrounding more compact Aβ plaques in the brain. Spatial transcriptomic imaging and pathway analysis of differentially expressed genes (DEGs) within myeloid cells demonstrate down‐regulated disease‐associated (DAM) pathways involving Aβ clearance, response to lipids, and macrophage activation within infected 5xFAD brains. CONCLUSIONS JHMV encephalitis induces dysregulated gene expression and myeloid cell responses to Aβ plaque burden in 5xFAD mouse brains.