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J. Biol. Chem., Vol. 279, Issue 52, 54518-54528, December 24, 2004

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Linking Alterations in Tau Phosphorylation and Cleavage during Neuronal Apoptosis^*

Armelle Rametti, Françoise Esclaire, Catherine Yardin, and Faraj Terro

From the EA 3842, Homéostasie Cellulaire et Pathologie, Department of Histology and Cell Biology, Faculty of Medicine, Limoges 87025, France

Neurofibrillary tangles (NFTs) are classic lesions of Alzheimer's disease. NFTs are bundles of abnormally phosphorylated tau, the paired helical filaments. The initiating mechanisms of NFTs and their role in neuronal loss are still unknown. Accumulating evidence supports a role for the activation of proteolytic enzymes, caspases, in neuronal death observed in brains of patients with Alzheimer's disease. Alterations in tau phosphorylation and tau cleavage by caspases have been previously reported in neuronal apoptosis. However, the links between the alterations in tau phosphorylation and its proteolytic cleavage have not yet been documented. Here, we show that, during staurosporine-induced neuronal apoptosis, tau first undergoes transient hyperphosphorylation, which is followed by dephosphorylation and cleavage. This cleavage generated a 10-kDa fragment in addition to the 17- and 50-kDa tau fragments previously reported. Prior tau dephosphorylation by a glycogen synthase kinase-3 inhibitor, lithium, enhanced tau cleavage and sensitized neurons to staurosporine-induced apoptosis. Caspase inhibition prevented tau cleavage without reversing changes in tau phosphorylation linked to apoptosis. Furthermore, the microtubule depolymerizing agent, colchicine, induced tau dephosphorylation and caspase-independent tau cleavage and degradation. Both phenomena were blocked by inhibiting protein phosphatase 2A (PP2A) by okadaic acid. These experiments indicate that tau dephosphorylation precedes and is required for its cleavage and degradation. We propose that the absence of cleavage and degradation of hyperphosphorylated tau (due to PP2A inhibition) may lead to its accumulation in degenerating neurons. This mechanism may contribute to the aggregation of hyperphosphorylated tau into paired helical filaments in Alzheimer's disease where reduced PP2A activity has been reported.

Received for publication, July 20, 2004 , and in revised form, October 7, 2004.

^* This work was supported by the Conseil Regional du Limousin and the Association France-Alzheimer. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 33-5-55-43-58-33; Fax: 33-5-55-43-58-93; E-mail: faraj.terro{at}unilim.fr.

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