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The Journal of Neuroscience, September 15, 1998, 18(18):7061-7074

Tau Cleavage and Dephosphorylation in Cerebellar Granule Neurons Undergoing Apoptosis

Nadia Canu¹, Laura Dus², Christian Barbato¹, Maria T. Ciotti², Claudio Brancolini³, Anna M. Rinaldi¹, Michal Novak^{4, 5}, Antonino Cattaneo⁴, Andrew Bradbury⁴, and Pietro Calissano^{1, 2}

¹ Dipartimento di Neuroscienze, Università di Roma Tor Vergata, 00173 Roma, Italy, ² Istituto di Neurobiologia, Consiglio Nazionale delle Ricerche, 00137 Roma, Italy, ³ Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie, AREA Science Park, 34142 Trieste, Italy, ⁴ International School for Advanced Studies, Neuroscience Program, 34013 Trieste, Italy, and ⁵ Institute of Neuroimmunology, Slovak Academy of Science, 84246 Bratislava, Slovak Republic

Cerebellar granule cells undergo apoptosis in culture after deprivation of potassium and serum. During this process we found that tau, a neuronal microtubule-associated protein that plays a key role in the maintenance of neuronal architecture, and the pathology of which correlates with intellectual decline in Alzheimer's disease, is cleaved. The final product of this cleavage is a soluble dephosphorylated tau fragment of 17 kDa that is unable to associate with microtubules and accumulates in the perikarya of dying cells. The appearance of this 17 kDa fragment is inhibited by both caspase and calpain inhibitors, suggesting that tau is an in vivo substrate for both of these proteases during apoptosis. Tau cleavage is correlated with disruption of the microtubule network, and experiments with colchicine and taxol show that this is likely to be a cause and not a consequence of tau cleavage.

These data indicate that tau cleavage and change in phosphorylation are important early factors in the failure of the microtubule network that occurs during neuronal apoptosis. Furthermore, this study introduces new insights into the mechanism(s) that generate the truncated forms of tau present in Alzheimer's disease.

Key words: apoptosis; tau; calpain; caspase; cerebellar granule neurons; Alzheimer's disease

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Copyright © 1998 Society for Neuroscience  0270-6474/98/18187061-14$05.00/0

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