Tau neuroinflammatory cascade. In early stages of tau structural metamorphosis, some proinflammatory cytokines (IL-1, IL6 and TNF-α) and chemokines (fractalkine) can modify tau phosphorylation patterns and thus change the structure and function of tau protein. The major sources of proinflammatory cytokines are activated microglia and astrocytes. Glial cells can be activated by different inducers, including misfolded tau protein. At this stage, however, the phosphorylated tau protein would not necessarily aggregate into the filamentous structures (A). In later stages, when misfolded hyperphosphorylated tau proteins form mature NFTs, inflammation could either accelerate or modify tangle formation. Several components of the brain's immune system, including cytokines and proteins of the complement pathway, have been shown to be involved in the molecular dialogue between activated glial cells and tangle-bearing neurons (B).