Figure 11.

Proposed mechanisms of tau pathogenesis. A, model for the majority of tau variants due to missense mutations that predominantly impair MT binding, resulting in increased unbound tau as depicted by arrows with solid lines. These altered tau properties may result in aberrant tau cellular distribution, reduced MT assembly/stability, and MT dynamics. An increased pool of unbound tau can convert into new conformers/oligomers that can be toxic and/or permissive to aggregated pathological inclusions. For these mutants, therapies that directly target MT dysfunctions and restore function are more likely to be beneficial. B, model associated with tau variants due to missense mutations that robustly potentiate tau aggregation, but also impair MT interactions. These mutants can lead to neuronal demise through two independent pathways depicted by arrows with solid lines and dashed lines. Therapies that target MT dysfunctions and tau aggregation are likely to have an impact on disease course for these types of mutants, but it is still unclear which would be the most beneficial.