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J. Biol. Chem., Vol. 281, Issue 1, 229-240, January 6, 2006

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Microtubule-associated Protein MAP1A, MAP1B, and MAP2 Proteolysis during Soluble Amyloid -Peptide-induced Neuronal Apoptosis

SYNERGISTIC INVOLVEMENT OF CALPAIN AND CASPASE-3^*

From the Lipidomix, JeuneÉquipe 2482, Laboratoire Médecine et Thérapeutique Moléculaire, Institut National Polytechnique de Lorraine, 54500 Vandoeuvre-lès-Nancy, France

A growing body of evidence supports the notion that soluble oligomeric forms of the amyloid -peptide (A) may be the proximate effectors of neuronal injuries and death in the early stages of Alzheimer disease. However, the molecular mechanisms associated with neuronal apoptosis induced by soluble A remain to be elucidated. We recently demonstrated the involvement of an early reactive oxygen species-dependent perturbation of the microtubule network (Sponne, I., Fifre, A., Drouet, B., Klein, C., Koziel, V., Pincon-Raymond, M., Olivier, J.-L., Chambaz, J., and Pillot, T. (2003) J. Biol. Chem. 278, 3437–3445). Because microtubule-associated proteins (MAPs) are responsible for the polymerization, stabilization, and dynamics of the microtubule network, we investigated whether MAPs might represent the intracellular targets that would enable us to explain the microtubule perturbation involved in soluble A-mediated neuronal apoptosis. The data presented here show that soluble A oligomers induce a time-dependent degradation of MAP1A, MAP1B, and MAP2 involving a perturbation of Ca²⁺ homeostasis with subsequent calpain activation that, on its own, is sufficient to induce the proteolysis of isoforms MAP2a, MAP2b, and MAP2c. In contrast, MAP1A and MAP1B sequential proteolysis results from the A-mediated activation of caspase-3 and calpain. The prevention of MAP1A, MAP1B, and MAP2 proteolysis by antioxidants highlights the early reactive oxygen species generation in the perturbation of the microtubule network induced by soluble A. These data clearly demonstrate the impact of cytoskeletal perturbations on soluble A-mediated cell death and support the notion of microtubule-stabilizing agents as effective Alzheimer disease drugs.

Received for publication, July 7, 2005 , and in revised form, October 12, 2005.

^* This work was supported in part by INSERM and by a grant from the Aventis French Network on Molecular Mechanisms in Alzheimer Disease. 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.

The on-line version of this article (available at http://www.jbc.org) contains a supplemental figure.

¹ Recipient of a fellowship from the Ministère de l'Enseignement Supérieur et de la Recherche and a grant from the Fondation pour la Recherche Médicale.

² To whom correspondence should be addressed: Lab. Médecine et Thérapeutique Moléculaire, Inst. National Polytechnique de Lorraine, 15 rue du Bois de la Champelle, 54500 Vandoeuvre-lès-Nancy, France. Tel.: 33-3-8367-8211; Fax: 33-3-8367-8999; E-mail: Thierry.Pillot{at}mtm.nancy.inserm.fr.

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