Pathological tau activates nuclear factor‐kappa B (NF‐κB) and drives neuroinflammation

Hyperphosphorylation and aggregation of tau is a pathological hallmark of Alzheimer’s disease and related tauopathies. Pathologically modified tau (pTau) displays varying degree of gain‐of‐toxic functions, in addition to loss of its normal homeostatic function in neurons. Several prior studies have suggested occurrence of innate immune activation in brain regions that spatio‐temporally overlap with pTau burden in brains of various tauopathies. Recent studies have suggested that once tau is hyperphosphorylated and misfolded, the neurons tend to expel pTau to the extracellular space, which is taken up by other neurons and results in trans‐neuronal propagation of pTau. We made a compelling discovery that en route to other neurons, pTau can also interact with and serve as an initial trigger to lead to microglial activation and neuroinflammation (Cell Reports 2021). However, it is not unclear if pTau driven innate immune activation involve canonical NF‐κB pathway.