Investigating the interactions between viral infection, Tau pathology, and neuroinflammation

Project Summary
Increasing evidence points to the neuroimmune system as a primary contributor to Alzheimer’s disease (AD).
Environmental factors that increase neuroinflammation, including viral infections, correlate with risk of AD;
however, the mechanisms by which microbial infections promote AD are not well understood. AD is defined by
the presence of two hallmark pathologies—extracellular senile plaques composed of aggregated amyloid beta
peptide (Aβ) and intracellular neurofibrillary tangles composed of the hyperphosphorylated microtubule
associated protein tau. Recent studies have suggested that Aβ may act as an antimicrobial peptide, in which
its aggregation can restrict microbial infection by trapping it in the extracellular space. We hypothesize that as
an intracellular protein, Tau may act as an antimicrobial peptide against viruses, which are obligate intracellular
pathogens. Our preliminary data shows that following intracranial inoculation with an attenuated strain of West
Nile virus, Kunjin virus (KUNV), Tau becomes hyperphosphorylated and aggregates. Furthermore, transgenic
mice expressing elevated levels of aggregation-prone Tau show reduced viral burden in their brains. Here we
propose to study the interactions between viral infection, Tau pathology, and neuroinflammation using a murine
model of encephalitic KUNV infection. Aim 1 will determine whether viral infection increases Tau pathology by
measuring aggregation, phosphorylation, and truncation. Aim 2 will assess the impact of Tau aggregation on
viral replication and whether Tau interacts directly with viral components. Aim 3 will examine the effect of Tau
pathology on the neuroinflammatory response to viral infection. Together, these experiments will determine
whether viral infection impacts the development of Tau pathology and the role of Tau pathology in modulating
the neuroimmune response to viral infection. Successful completion of this project will establish a mechanistic
link between AD and viral pathogens.