Soluble Amyloid Precursor Protein Alpha Interacts with alpha3-Na, K-ATPAse to Induce Axonal Outgrowth but Not Neuroprotection: Evidence for Distinct Mechanisms Underlying these Properties

Emilie Dorard1,2 & Stéphanie Chasseigneaux1,3 & Lucie Gorisse-Hussonnois1 & Cédric Broussard4 & Thierry Pillot2 & Bernadette Allinquant1


1 /  UMR_S894 INSERM, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, 75014 Paris, France
2 /  SynAging, 54500Vandoeuvre-les, Nancy, France
3 / INSERM U1144, Université Paris Descartes and Université Paris Diderot UMR-S 1144, 75006 Paris, France
4 / Plate-forme Protéomique, Université Paris Descartes 3P5, Institut Cochin, 75014 Paris, France # Springer Science+Business Media, LLC 2017

 


Abstract

Amyloid precursor protein (APP) is cleaved not only to generate the amyloid peptide (Aß), involved in neurodegenerative processes, but can also be metabolized by alpha secretase to produce and release soluble Nterminal APP (sAPPα), which has many properties including the induction of axonal elongation and neuroprotection. The mechanisms underlying the properties of sAPPα are not known. Here, we used proteomic analysis of mouse cortico-hippocampal membranes to identify the neuronal specific alpha3 (α3)-subunit of the plasma membrane
enzyme Na, K-ATPase (NKA) as a new binding partner of sAPPα. We showed that sAPPα recruits very rapidly clusters of α3-NKA at neuronal surface, and its binding triggers a cascade of events promoting sAPPα- induced axonal outgrowth. The binding of sAPPα with α3-NKA was not observed for sAPPα-induced Aß1-42 oligomers neuroprotection, neither the downstream events particularly the interaction of sAPPα with APP before endocytosis, ERK signaling, and the translocation of SET from the nucleus to the plasma membrane. These data suggest that the mechanisms of the axonal growth promoting and neuroprotective properties of sAPPα appear to be specific and independent. The signals at the cell surface specific to trigger these mechanisms require further study.

Keywords : Soluble amyloid precursor protein alpha . alpha3-Na, K-ATPase . Neuron . Axonal elongation . Neuroprotection . SET


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