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J Biol Chem. 2002 Jun 7;277(23):20979-90. Epub 2002 Mar 4.

Amyloid precursor protein family-induced neuronal death is mediated by impairment of the neuroprotective calcium/calmodulin protein kinase IV-dependent signaling pathway.

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  • 1Université Louis Pasteur, Faculté de Médecine, EA 3433 Molecular signaling and neurodegeneration, 67000 Strasbourg, France.


The aberrant metabolism of beta-amyloid precursor protein (APP) and the progressive deposition of its derived fragment beta-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 beta-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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