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The Journal of Neuroscience, November 19, 2003, 23(33):10662-10671

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Cellular/Molecular
Reduction of Detyrosinated Microtubules and Golgi Fragmentation Are Linked to Tau-Induced Degeneration in Astrocytes

Yasumasa Yoshiyama, Bin Zhang, Jennifer Bruce, John Q. Trojanowski, and Virginia M.-Y. Lee

Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Institute on Aging, University of Pennsylvania, Philadelphia, Pennsylvania 19104

Several human neurodegenerative diseases are associated with abnormal accumulations of aggregated tau proteins and glial degeneration in astrocytes, but the mechanism whereby tau proteins cause astrocytic degeneration is unclear. Here, we analyzed the biological consequences of overexpressing the longest human tau isoform in primary cultures of rat astrocytes using adenoviral-mediated gene transfer. Significantly, we found specific decreases in stable detyrosinated [glutamate (Glu)] microtubules (MTs) with concomitant increases in tubulin biosynthesis and the accumulation of acetylated, tyrosinated, - and -tubulin. The consequences of this selective reduction in stable Glu-MTs included contemporaneous decreases in kinesin levels, collapse of the intermediate filament network, progressive disruption of kinesin-dependent trafficking of organelles, fragmentation of the Golgi apparatus that culminated in atrophy, and non-apoptotic death of astrocytes. These results suggest that reduced stable Glu-MTs is a primary consequence of tau accumulation that initiates mechanisms underlying astrocyte dysfunction and death in human neurodegenerative glial tauopathies.

Key words: Alzheimer; astrocyte; astroglial; degeneration; Golgi; microtubule; tau

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Received May 22, 2003; revised September 11, 2003; accepted September 15, 2003.

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