Published 18 March 2002. doi:10.1083/jcb1566iti5
© The Rockefeller University Press,
0021-9525/2002/3/938-a $5.00
The Journal of Cell Biology, Volume 156, Number 6, March 18, 2002 938-a-938
Finding the dark side of tau
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APP transport (top) is inhibited by excess tau protein (bottom).
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On page 1051, Stamer et al. have uncovered what may be a critical early step in the pathogenesis of Alzheimer's disease and a previously unappreciated regulatory system for microtubule-based motors. The work focuses on the microtubule-associated protein tau, which is thought to cause the pathological changes seen in some neurodegenerative diseases. The prevailing view is that tau stabilizes microtubules, and disease results when the protein detaches from microtubules and aggregates into paired helical filaments. According to the authors, the opposite situation—having too much tau attached to microtubules—may be just as bad.
Overexpressing tau in neuroblastoma cell lines, primary hippocampal neurons, or retinal ganglion cells leaves microtubules intact. Rather than forming filaments, the overexpressed tau binds to microtubules and appears to lay the groundwork for neurodegeneration. Excess tau causes the depletion of mitochondria and peroxisomes from the cells' processes, retarding growth and increasing the cells' sensitivity to oxidative stress. The transport of Golgi-derived vesicles into axons is inhibited, and neurofilament proteins and vesicles carrying the amyloid precursor protein (APP) accumulate in the cell body. These changes are likely to increase the production of toxic amyloid Aß peptides, a hallmark of Alzheimer's disease.
Thus, whereas low levels of tau are necessary for microtubule stability, higher levels interfere with transport. Detachment of tau from microtubules and aggregation of tau into filaments might be a later consequence of the trafficking problems caused by excess tau attaching to microtubules. The results also suggest a novel regulatory system for microtubule-based motors, in which tau and other proteins on microtubules might act as roadblocks that determine the rate of vesicle trafficking. 
Alan W. Dove
alanwdove{at}earthlink.net
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