Microtubule-associated protein MAP1A, MAP1B, and MAP2 proteolysis during soluble amyloid β-peptide-induced neuronal apoptosis -: Synergistic involvement of calpain and caspase-3

A growing body of evidence supports the notion that soluble oligomeric forms of the amyloid beta-peptide (A beta) 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 beta 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 beta-mediated neuronal apoptosis. The data presented here show that soluble A beta 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 beta-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 beta. These data clearly demonstrate the impact of cytoskeletal perturbations on soluble A beta-mediated cell death and support the notion of microtubule-stabilizing agents as effective Alzheimer disease drugs.