ApoE4 has been associated with AD-related tau pathologies in both humans and transgenic and gene-targeted mice1,7,17,18. The current study shows that apoE4 in fact increases p-tau levels in cultured human neurons. ApoE4/4 neurons in culture were positive for multiple p-tau-specific monoclonal antibodies (e.g, AT8, AT180, AT270, and PHF1), suggesting hyperphosphorylation of tau. Furthermore, p-tau in apoE4/4 human neurons was largely mislocalized to the soma and dendrites, as seen in AD brains. Again, conversion of apoE4 to apoE3 by gene editing significantly lowered p-tau levels, consistent with a specific effect of apoE4. It has been suggested that Aβ accumulation leads to increase in phosphorylation and accumulation of tau24,25. However, we showed that treatment of apoE4/4 human neurons with a β-secretase or a γ-secretase inhibitor drastically reduced Aβ40 and Aβ42 levels without altering p-tau levels at all. These findings strongly suggest that apoE4 induces p-tau accumulation in an Aβ-independent manner in human neurons at least in culture. In line with this conclusion, a recent study suggests that apoE4 also has an Aβ-independent and gain-of-toxic effect on tau-mediated neurodegeneration in a tauopathy model of mice expressing mutant human tau47.
