Transient increase in sAPPa secretion in response to Ab1e42 oligomers: an attempt of neuronal self-defense?

Christiane Rose a, Emilie Dorard a,b, Mickael Audrain c, Lucie Gorisse-Hussonnois a, Nathalie Cartier c, Jérome Braudeau d, Bernadette Allinquant a,

a /  UMR_S894, INSERM, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France
b /  SynAging, Nancy, France
c / INSERM UMR1169, Université Paris-Sud, Paris-Saclay, Orsay, and CEA, DSV, I2BM, MIRCen, Fontenay-aux-Roses, France
d  / CEA, DRF, Institut François Jacob, MIRCen, Fontenay-aux-Roses, France


Amyloid precursor protein (APP), a key molecule of Alzheimer disease, is metabolized in 2 antagonist pathways generating the soluble APP alpha (sAPPa) having neuroprotective properties and the beta amyloid (Ab) peptide at the origin of neurotoxic oligomers, particularly Ab1e42. Whether extracellular Ab1e42 oligomers modulate the formation and secretion of sAPPa is not known.We report here that the addition of Ab1e42 oligomers to primary cortical neurons induced a transient increase in a-secretase activity and secreted sAPPa 6e9 hours later. Preventing the generation of sAPPa by using small interfering RNAs (siRNAs) for the a-secretases ADAM10 and ADAM17 or for APP led to increased Ab1e42 oligomereinduced cell death after 24 hours. Neuronal injuries due to oxidative stress or growth factor deprivation also generated sAPPa 7 hours later. Finally, acute injection of Ab1e42 oligomers into wildtype mouse hippocampi induced transient secretion of sAPPa 48e72 hours later. Altogether, these data suggest that neurons respond to stress by generating sAPPa for their survival. These data must be taken into account when interpreting sAPPa levels as a biomarker in neurological disorders.

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