The first line of defense against tau accumulation is the E3 ligase CHIP, which mediates the ubiquitination of tau (primarily in its phosphorylated form), in collaboration with Hsp70 and Hsp90 (Figure 4).111 An in vitro study showed that the E2 enzyme Ube2w can also mediate E3-independent ubiquitination of tau.112 However, ubiquitinated tau is not a good substrate of the proteasome and thus accumulates as detergent-resistant aggregates, leading to the formation of neurofibrillary tangles in AD. This evidence concerns the gene MAPT and Neurofibrillary tangles.