Fig 1: Model proposing the independent actions of pathological tau within a cell. In the cytoplasm, an imbalance of kinase and phosphatase activity contributes to the hyperphosphorylation of tau. This hyperphosphorylated tau can sequester normal tau to form aggregates. This behavior results in destabilization of the microtubule network and the formation of intracellular vacuoles (left). We have now demonstrated that PH-tau is able to translocate into the nucleus (left & right). This results in disruption of the nuclear lamina and mislocalization of the nuclear protein TDP-43 (red ovals) to the cytoplasm, ultimately inducing cellular death (right). It is currently hypothesized that PH-tau can propagate in a prion-like manner. We have shown that monomeric tau can be uptaken by healthy neurons (Morozova et al., 2019), and other reports have seen the same for oligomeric tau (Guo and Lee, 2013; Calafate et al., 2015; Evans et al., 2018). This uptake of PH-tau by healthy cells could spread the cytoskeletal and nuclear pathologies.