Figure 8.

Involvement of PKR in tau‐dependent neurodegenerative processes. A. Healthy CNS environment. PKR is constitutively expressed at low levels and mainly exists in its inactive state. Tau is associated with the axon where it stabilizes microtubules. B. Inflammation due to eg, CTE or systemic and cerebral infections initiates activation of the innate immune response, resulting in glial release of pro‐inflammatory cytokines TNF‐α, IL‐1 and IFN‐γ that activate PKR, and type I interferons involved in enhanced PKR expression. Activation of PKR can directly increase levels of abnormally phosphorylated tau resulting in decreased microtubule binding, increased microtubule instability, re‐localization of tau outside the axon and an increased propensity of tau to undergo self‐assembly into tangles. Such temporally defined periods of inflammation‐induced PKR activation may contribute enough to tip the balance and initiate tau pathology.