Characterization of effects of a neurotropic murine coronavirus infection on Alzheimer's disease neuropathology of 5xFAD mice

BackgroundRecent studies revealed key immunological mechanisms within the central nervous system (CNS) that contribute to Alzheimers disease pathology. Additionally, analyses of human AD datasets have also associated viral encephalitis exposure (i.e., viral-induced neuroinflammation) with the development of AD and dementia, highlighting the need to better understand how viral encephalitis and neuroimmune mechanisms within the brain may impact AD pathologies such as A{beta} plaque deposition. Intracranial infection of susceptible mice with the neurotropic JHM strain of murine coronavirus (JHMV) results in acute encephalomyelitis characterized by viral infection of glia and a robust inflammatory response comprised of monocytes/macrophages and T cells that aid in controlling viral replication. MethodsTo determine how coronavirus-induced encephalitis may impact established A{beta} plaque deposition, we intracranially inoculated JHMV into aged 5xFAD model of amyloidosis. We utilize immunohistochemical and biochemical analysis to assess the impact on existing A{beta} pathology. We also utilize spatial transcriptomic imaging to explore how viral encephalitis affects cellular responses to plaque pathology with single-cell resolution. ResultsIn aged 5xFAD mice, JHMV-induced encephalitis at 12 days p.i. resulted in minimal changes to overall A{beta} protein within the brain. However, viral encephalitis induces CD4+ and CD8+ T cell infiltration and more Lgals3/MAC2-expressing macrophages surrounding dense-core A{beta} plaques, which appear more compacted in JHMV-infected 5xFAD brains compared to uninfected 5xFAD controls. We compared gene expression within JHMV-infected 5xFAD mice and uninfected controls to identify distinct cellular responses to A{beta} plaques that differed. Utilizing differential gene expression and pathway analysis, we found that viral encephalitis increased the proportion of myeloid cells in the 5xFAD brain, which also showed down-regulated disease-associated (DAM) pathways involving A{beta} clearance, response to lipids, and macrophage activation within the post-encephalitis 5xFAD brains. ConclusionsTogether, these findings suggest an attenuated myeloid cell response to A{beta} plaque burden in 5xFAD mice following acute viral encephalitis. Future experiments aim to further dissect inflammatory mechanisms between infiltrating myeloid cells, T cells, and the progression of A{beta} and tau pathology. Data derived from these experiments will further elucidate the viral-induced neuroimmune mechanisms that affect AD pathology and offer an opportunity to determine how these neuropathologic changes, such as subsequent neuronal damage, occur.