MAPT and Alzheimer disease: First, insoluble NFTs may be toxic and lead to neuron death and cognitive dysfunction in AD; second, soluble species of misfolded, hyperphosphorylated tau may become toxic when they accumulate in inappropriate cellular compartments, whereas NFTs exert a protective effect by serving as a sink for these toxic species; and in the third view, soluble forms of pathological tau and insoluble NFTs are both toxic to cells in various ways and time scales (Kopeikina et al., 2012).