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

Amyloid precursor protein (APP) is cleaved not only to generate the amyloid peptide (A beta), involved in neurodegenerative processes, but can also be metabolized by alpha secretase to produce and release soluble N-terminal APP (sAPP alpha), which has many properties including the induction of axonal elongation and neuroprotection. The mechanisms underlying the properties of sAPP alpha are not known. Here, we used proteomic analysis of mouse cortico-hippocampal membranes to identify the neuronal specific alpha3 (alpha 3)-subunit of the plasma membrane enzyme Na, K-ATPase (NKA) as a new binding partner of sAPP alpha. We showed that sAPP alpha recruits very rapidly clusters of alpha 3-NKA at neuronal surface, and its binding triggers a cascade of events promoting sAPP alpha-induced axonal outgrowth. The binding of sAPP alpha with alpha 3-NKA was not observed for sAPP alpha-induced A beta 1-42 oligomers neuroprotection, neither the downstream events particularly the interaction of sAPP alpha 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 sAPP alpha appear to be specific and independent. The signals at the cell surface specific to trigger these mechanisms require further study.