Subsequently, in patients without mutations, similar accumulations of 4R-tau were found to lead to diverse clinical phenotypes also with cognitive, behavioral, and motor involvement, collectively termed 4R-tauopathies, which include progressive supranuclear palsy (PSP), [18] corticobasal degeneration (CBD) [19], and argyrophilic grain disease (AGD) [20]. Accumulation of the 3R isoforms has also been linked to pathologic aggregation, as seen in Pick’s disease (a 3R-tauopathy), and a limited number of MAPT mutations. [21] Equal expression of 3R- and 4R-tau, is found in AD and chronic traumatic encephalopathy (CTE). Although tau inclusions are present in a group of neurodegenerative diseases, patients with different tauopathies show distinctive clinical symptoms and patterns of tau aggregation. Tau pathology is presented in various forms, in different brain regions, cell types, as well as subcellular localization depending on the disease [22]. Tau isoforms have diverse contributions and specific filament conformations lead to ultrastructure conformation in each of the tauopathies [23,24]. The implication is that a particular tau aggregate strain is the culprit in each specific Tauopathy. The pathological diversity of tauopathies imposes a challenge in finding a common treatment that can be applied to all diseases in which tau plays a toxic role.
