MAPT and neurodegenerative disease: Perhaps a “one hit” model, which predicts that abnormally misfolded tau is both necessary and sufficient for induction of toxicity, as was suggested to account for the progression of several neurodegenerative diseases (Clarke et al., 2000, modified by Clarke and Lumsden, 2005), needs to be replaced by a “two hit” model, where another event, which is not toxic per se, is required for tau to cause cell death.