Amyloid precursor protein family-induced neuronal death is mediated by impairment of the neuroprotective calcium/calmodulin protein kinase IV-dependent signaling pathway.
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.
Mbebi
Corinne
C
Université Louis Pasteur, Faculté de Médecine, EA 3433 Molecular signaling and neurodegeneration, 67000 Strasbourg, France.
Sée
Violaine
V
Mercken
Luc
L
Pradier
Laurent
L
Müller
Ulrike
U
Loeffler
Jean-Philippe
JP
D016564:Amyloid beta-Protein Precursor / Q000502:physiology*; D000818:Animals; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology*; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology* / Q000201:enzymology; D018384:Oxidative Stress; D015398:Signal Transduction
D016564:Amyloid beta-Protein Precursor; D017362:Cyclic AMP Response Element-Binding Protein; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C517685:Camk4 protein, mouse; D020558:GTP Phosphohydrolases