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J. Biol. Chem., Vol. 277, Issue 23, 20979-20990, June 7, 2002

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Amyloid Precursor Protein Family-induced Neuronal Death Is Mediated by Impairment of the Neuroprotective Calcium/Calmodulin Protein Kinase IV-dependent Signaling Pathway^*

Corinne Mbebi, Violaine Sée, Luc Mercken^§, Laurent Pradier^§, Ulrike Müller^¶, and Jean-Philippe Loeffler

From the  Université Louis Pasteur, Faculté de Médecine, EA 3433 Molecular signaling and neurodegeneration, 67000 Strasbourg, France, the ^§ Department of Neurodegenerative Disease Group, Aventis Pharma, 94400 Vitry-sur Seine, France, and the ^¶ Department of Neurochemistry, Max-Planck Institute for Brain Research, D-60528 Frankfurt, Germany

The aberrant metabolism of -amyloid precursor protein (APP) and the progressive deposition of its derived fragment -amyloid peptide are early and constant pathological hallmarks of Alzheimer's disease. Because APP is able to function as a cell surface receptor, we investigated here whether a disruption of the normal function of APP may contribute to the pathogenic mechanisms in Alzheimer's disease. To this aim, we generated a specific chicken polyclonal antibody directed against the extracellular domain of APP, which is common with the -amyloid precursor-like protein type 2. Exposure of cultured cortical neurons to this antibody (APP-Ab) induced cell death preceded by neurite degeneration, oxidative stress, and nuclear condensation. Interestingly, caspase-3-like protease was not activated in this neurotoxic action suggesting a different mode of cell death than classical apoptosis. Further analysis of the molecular mechanisms revealed a calpain- and calcineurin-dependent proteolysis of the neuroprotective calcium/calmodulin-dependent protein kinase IV and its nuclear target protein cAMP responsive element binding protein. These effects were abolished by the G protein inhibitor pertussis toxin, strongly suggesting that APP binding operates via a GTPase-dependent pathway to cause neuronal death.

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