Tau in Alzheimer's disease

doi:10.1016/S0962-8924(98)01368-3

Trends in Cell Biology

Volume 8, Issue 11, 1 November 1998, Pages 425-427

https://doi.org/10.1016/S0962-8924(98)01368-3 Get rights and content

Abstract

Neurofibrillar protein aggregates containing tau are one of the major hallmarks of Alzheimer's disease (AD). In normal cells, tau stabilizes axonal microtubules, which are the tracks for intracellular traffic. In AD, tau becomes abnormally phosphorylated, aggregates into paired helical filaments and loses its ability to maintain the microtubule tracks. There is renewed interest in tau as a causative factor in neurodegenerative disease based on recently discovered mutations in the gene encoding tau. This article discusses how changes in tau protein could lead to retraction of neuronal processes and thus cell death and argues that tau pathology, rather than β-amyloid, might be the most reliable indicative factor for AD.

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.

•
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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Trends in Cell Biology

ForumTau in Alzheimer's disease

Abstract

Section snippets

Physiological functions of tau

Pathological alterations of tau in AD

A role for tau in AD?

Authors' note

Acknowledgements

Trends Biochem. Sci.

Neuron

Neurobiol. Aging

Trends Neurosci.

Int. Rev. Cytol.

FEBS Lett.

Neurobiol. Aging

J. Biol. Chem.

Arch. Neurol.

J. Neuropathol. Exp. Neurol.

Neurobiol. Aging

Acta Neuropathol.

J. Neuropathol. Exp. Neurol.

Trends Cell Biol.

Ann. Neurol.

Proc. Natl. Acad. Sci. U. S. A.

Nature

Neuroscientist

FASEB J.

Forum
Tau in Alzheimer's disease