Trends in Cell Biology
ForumTau in Alzheimer's disease
Section snippets
Physiological functions of tau
Tau is one of the microtubule-associated proteins (MAPs) that stabilize neuronal microtubules for their role in the development of cell processes, establishment of cell polarity and intracellular transport[10]. Tau occurs mainly in axons (in contrast to the somatodendritic MAP2). A single gene encodes tau, which generates six isoforms, of 352 to 441 amino acid residues, in the human central nervous system by alternative splicing (Fig. 1), plus a larger variant in peripheral nerves[11]. The
Pathological alterations of tau in AD
In AD, the properties of tau change in several ways.
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AD-tau shows an abnormal `hyperphosphorylation' at many sites13, 14, 26. Some increase occurs also in foetal tissue and in mitotic cells, leading to the hypothesis that `mitotic' signals received by differentiated neurons might cause hyperphosphorylation of tau and, later, death by apoptosis. Many of the abnormal phosphorylation sites are at Ser-Pro or Thr-Pro motifs; this explains why various antibodies raised against AD-tau react with such
A role for tau in AD?
The above observations can be placed in a hypothetical scheme (Fig. 2): inappropriate signals lead to an imbalance of kinases/phosphatases, hyperphosphorylation of tau, its detachment from microtubules, microtubule breakdown, aggregation of tau into PHFs, breakdown of intracellular transport and degeneration of neurons. However, many intermediate steps are still unknown. For example, the effect of different kinases on tau has been examined in vitro and in cell models[10], but which of them is
Authors' note
Debates on mechanisms of neuronal degeneration in Alzheimer's disease held during the recent International Alzheimer congress in Amsterdam can be found on the Internet at: http://www.alzforum.org/members/index.html.
Acknowledgements
We thank J. Biernat and A. Ebneth for help in designing the figures. Our work is supported by Deutsche Forschungsgemeinschaft (Alzheimer Research Group, Hamburg).
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