From Protein Tangles to Genetic Variants: The Central Role of Tau in Neurodegenerative Disease

Since the first description in 1907 of intracellular tangles in degenerating neurons in the brain of a woman who had suffered from progressive dementia by Alois Alzheimer, research in the microtubule-associated protein tau (MAPT or tau), the major component of these intracellular deposits, and its involvement in neurodegenerative processes, has undergone a shift in paradigm. Originally regarded by many scientists as a second string player in Alzheimer’s disease, it is now becoming increasingly clear that tau plays a crucial role in many neurodegenerative diseases. The discovery of neurofibrillary tangles in other progressive nervous system disorders – now commonly referred to as tauopathies – as well as the more recent association of MAPT genetic variants with Parkinson’s disease have contributed to this heightened interest. In this chapter, we will review the developments of tau research from the beginnings to recent advances. We will focus on the increasing evidence implicating tau as a major player in neurodegeneration as well as on efforts to establish and optimize animal models of tauopathy to understand the molecular basis of this group of neurodegenerative diseases. In the final chapter section we will look forward and summarize the potential strategies for therapeutic strategies targeting tau for the treatment of tauopathic neurodegenerative diseases.