Alois Alzheimer couldn't have chosen a name more appropriate than neurofibrillary tangles when one hundred years ago (Alzheimer, 1906) he presented this histopathological hallmark of the progressive dementing disorder, which got named after him as
Alzheimer disease. Both, the structure and as well as the molecular composition of neurofibrillary tangles have baffled neuroscientists for many years. It was not till 1963 when with the help of the electron microscope the tangles were found to be made up of paired helical filaments (PHF). It took another 23 years before
microtubule associated protein tau was immunohistochemically identified as the part of neurofibrillary tangles (Grundke-lqbal, 1986 a). The same year it was shown that
tau protein in
Alzheimer disease brain was abnormally hyperphosphorylated (Grundke-Iqbal, 1986 b). In 1988 Michal Novak, Cesar Milstein and Claude Wischik produced
monoclonal antibody that was able to recognize then unknown
protein in PHF. The antibody (MN423) allowed its isolation and let to full molecular characterization as
protein tau. These studies provided molecular proof that
tau protein was the major and an integral component of the PHF (Wischik et al, 1988 a, b, Goedert et al, 1988, Novak et al, 1989, 1991). Over the years the significance of tau pathology for the
neurodegenerative diseases was discussed and often questioned. However, detailed studies of the maturation and distribution of NFTs, showing correlation with degree of
cognitive decline and memory impairment in
Alzheimer's disease (Braak and Braak, 1991), together with discovery of tau gene mutations causing fronto-temporal
dementia in many families (Hutton et al, 1998) promoted tau as the major pathogenic force in neurodegenerative cascade. Further studies focused on tau dysfunctions revealed truncation and phosphorylation as two major posttranslational modifications responsible for toxic gain of function as an underlying cause of
tauopathies including
Alzheimer's disease (Alonso et al, 1996, Novak et al, 1989, 1991, 1993, Avila et al, 2006). Recently, in vivo experiments using transgenic expression of conformationally modified truncated tau showed that truncation is able to drive neurofibrillary pathology ofAlzheimer's type (Zilka et al, 2006). Finally, after one hundred years the exact nature of the neurofibrillary tangles and their role in neurodegeneration is beginning to be unraveled.