Tau proteins are expressed from a single gene (MAPT) on chromosome 17, resulting in six isoforms after alternative splicing that differ by N-terminal insertions and the number of repeats of microtubule binding repeat (MTBR) domains at the carboxy-terminal. [11] Importantly, three- or four-repeat MTBR isoforms (3R-tau or 4R-tau) arise from inclusion or exclusion of exon 10, and in the healthy adult brain 3R- and 4R-tau proteins are equally expressed [14]. In 1998, thirteen families with a clinical syndrome with cognitive, behavioral, and motor symptoms called frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) were found to have MAPT mutations that increased expression and aggregation of 4R-tau isoforms, [15-17] and these patients provided the first direct evidence for a causal link between tau dysfunction and neurodegenerative disease.
