Transient increase in sAPPα secretion in response to Aβ1–42 oligomers: an attempt of neuronal self-defense?

Abstract

Amyloid precursor protein (APP), a key molecule of Alzheimer disease, is metabolized in 2 antagonist pathways generating the soluble APP alpha (sAPPα) having neuroprotective properties and the beta amyloid (Aβ) peptide at the origin of neurotoxic oligomers, particularly Aβ1–42. Whether extracellular Aβ1–42 oligomers modulate the formation and secretion of sAPPα is not known. We report here that the addition of Aβ1–42 oligomers to primary cortical neurons induced a transient increase in α-secretase activity and secreted sAPPα 6–9 hours later. Preventing the generation of sAPPα by using small interfering RNAs (siRNAs) for the α-secretases ADAM10 and ADAM17 or for APP led to increased Aβ1–42 oligomer–induced cell death after 24 hours. Neuronal injuries due to oxidative stress or growth factor deprivation also generated sAPPα 7 hours later. Finally, acute injection of Aβ1–42 oligomers into wild-type mouse hippocampi induced transient secretion of sAPPα 48–72 hours later. Altogether, these data suggest that neurons respond to stress by generating sAPPα for their survival. These data must be taken into account when interpreting sAPPα levels as a biomarker in neurological disorders.