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

Mol Neurobiol. 2018 Jul;55(7):5594-5610. doi: 10.1007/s12035-017-0783-0. Epub 2017 Oct 5.

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 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.

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

MeSH terms

  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • Axons / metabolism*
  • Cell Membrane / metabolism
  • DNA-Binding Proteins
  • Endocytosis
  • Histone Chaperones
  • Humans
  • MAP Kinase Signaling System
  • Mice, Inbred C57BL
  • Models, Biological
  • Neurites / metabolism
  • Neuroprotection*
  • Oncogene Proteins / metabolism
  • Peptide Fragments / metabolism*
  • Protein Binding
  • Sodium-Potassium-Exchanging ATPase / metabolism*
  • Solubility

Substances

  • APP protein, human
  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • DNA-Binding Proteins
  • Histone Chaperones
  • Oncogene Proteins
  • Peptide Fragments
  • SET protein, mouse
  • Atp1a3 protein, mouse
  • Sodium-Potassium-Exchanging ATPase