N-terminal tau truncation in the pathogenesis of Alzheimer's disease (AD): Developing a novel diagnostic and therapeutic approach

Tau truncation occurs at early stages during the development of human Alzheimer's disease (AD) and other tauopathy dementias. Tau cleavage, particularly in its N-terminal projection domain, is able to drive per se neurodegeneration, regardless of its pro-aggregative pathway(s) and in fragment(s)-dependent way. In this short review, we highlight the pathological relevance of the 20-22 kDa NH₂-truncated tau fragment which is endowed with potent neurotoxic “gain-of-function” action(s), both in vitro and in vivo. An extensive comment on its clinical value as novel progression/diagnostic biomarker and potential therapeutic target in the context of tau-mediated neurodegeneration is also provided.