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
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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 N-terminal 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.
KeywordsSoluble amyloid precursor protein alpha alpha3-Na, K-ATPase Neuron Axonal elongation Neuroprotection SET
We thank Luc Camoin and François Guillonneau for their supervision and comments on the proteomic analysis. This work was supported by the Institut National de la Santé et de la Recherche Médicale, France and by SynAging, Nancy, France.
Compliance with Ethical Standards
The protocol of animal anesthesia was carried out in compliance with French law in strict accordance with the recommendations of the European Economic Committee (63/2010) and was approved by the local ethics committee (Direction Départementale des Services Vétérinaires de Paris, Service de la Protection de Santé Animale et de la Protection de l’Environnement).
Conflict of Interest
The authors declare that they have no conflicts of interest.
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