Sci. Aging Knowl. Environ., 20 March 2002
Vol. 2002, Issue 11, p. nw38
[DOI: 10.1126/sageke.2002.11.nw38]


The Halting Way of Tau: Impeded traffic in nerve cells might occur early in Alzheimer's disease (Neurodegenerative disease)

Mary Beckman;2002/11/nw38

Key Words: transport • APP • A{beta} • kinesin-like motors • microtubule-associated protein (MAP) • frontotemporal dementia • tauopathy

Abstract: Like too many stop signs, overabundance of a protein called tau hampers traffic traveling down nerve cell projections, according to new work. As a result, cellular vehicles that haul energy and maintenance equipment can't get supplies to the neurons' tips. Tau pops up in several neurodegenerative disorders, and the research suggests that this inhibition of transport might underlie some of the damage done by the protein.

Abnormal brain structures called plaques and tangles characterize Alzheimer's disease (see "Detangling Alzheimer's Disease"). Scientists know that tau resides in tangles, but they hotly debate how the cellular snarls develop and contribute to neurodegeneration. Tau normally attaches to and stabilizes microtubules, long protein beams that reinforce fingerlike projections called neurites, which foster cell-to-cell communication. Microtubules also serve as tracks along which proteins and organelles travel to the far reaches of the neurites. Mutations in tau can lead to Alzheimer-like syndromes; most such mutations liberate tau, causing microtubules to fall apart and neurites to shrink. Some researchers suggest that this loss of microtubules initiates the eventual collapse of nerve cells in tau-related disorders. Tangles, in this view, are a byproduct of the real trouble. Indeed, some mutations in tau cause symptoms that mimic Alzheimer's disease--yet afflicted brains can be tangle-free.

To investigate how neurodegeneration could be caused by warped interactions between tau and microtubules, Stamer and colleagues overproduced tau in neural cancer cells and in primary neurons cultured from rats, mice, and chickens. Doubling the amount of tau prevented organelles such as mitochondria from moving into the neurites: The number of mitochondria and peroxisomes--sacks full of molecules that protect against oxidative damage--dropped severalfold in the cellular extremities. The cells also lost the ability to withstand oxidative stress (see "The Two Faces of Oxygen"); hydrogen peroxide caused the percentage of tau-glutted cells that sported long neurites to plummet from 9.9% to 0.3%. In contrast, only half of the normal cells lost their extensions. The results suggest that excess tau meddles with transport operations inside neurons by blocking microtubule tracks, causing damage similar to that seen when mutated tau destabilizes the tracks. Finally, the team members wanted to test what effect, if any, too much tau had on {beta}-amyloid precursor protein (APP), the unprocessed version of the protein that composes Alzheimer's plaques. Tau overproduction caused APP to collect in the cell body, where protein processing occurs. The researchers propose that such neurons produce abnormally large amounts of the harmful spawn of APP.

Tau-based traffic inhibition and associated neurite disintegration might represent an early event in Alzheimer's disease and tau-linked neurodegenerative disorders, the researchers suggest--one that occurs before noticeable brain pathologies appear. Neurologist Kenneth Kosik of Harvard Medical School in Boston says that the idea is interesting, "though it's not proven. But it does support the notion of 'pretangle-like' cells that look like they're on the way to neurodegenerative disease." If further research shows that the tau-induced roadblock is the way, perhaps it will lead Alzheimer's investigators to enlightenment.

--Mary Beckman

K. Stamer, R. Vogel, E. Thies, E. Mandelkow, E.-M. Mandelkow, Tau blocks traffic of organelles, neurofilaments, and APP vesicles in neurons and enhances oxidative stress. J. Cell Biol. 156, 1051-1063 (2002). [Abstract] [Full Text]

Citation: M. Beckman, The Halting Way of Tau: Impeded traffic in nerve cells might occur early in Alzheimer's disease (Neurodegenerative disease). Science's SAGE KE (20 March 2002),;2002/11/nw38

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