cGMP Favors the Interaction Between APP and BACE1 by Inhibiting Rab5 GTPase Activity

Sci Rep. 2020 Jan 28;10(1):1358. doi: 10.1038/s41598-020-58476-8.

Abstract

We previously demonstrated that cyclic guanosine monophosphate (cGMP) stimulates amyloid precursor protein (APP) and beta-secretase (BACE1) approximation in neuronal endo-lysosomal compartments, thus boosting the production of amyloid-β (Aβ) peptides and enhancing synaptic plasticity and memory. Here, we further investigated the mechanism by which cGMP regulates the subcellular localization of APP and BACE1, finding that the cyclic nucleotide inhibits the activity of Rab5, a small GTPase associated with the plasma membrane and early endosomes. Accordingly, we also found that expression of a dominant-negative Rab5 mutant increases both APP-BACE1 approximation and Aβ extracellular levels, therefore mimicking the effects induced by cGMP. These results reveal a functional correlation between the cGMP/Aβ pathway and the activity of Rab5 that may contribute to the understanding of Alzheimer's disease pathophysiology.

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Amyloid Precursor Protein Secretases / genetics
  • Amyloid Precursor Protein Secretases / metabolism*
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • Aspartic Acid Endopeptidases / genetics
  • Aspartic Acid Endopeptidases / metabolism*
  • Cell Line
  • Cell Membrane / genetics
  • Cell Membrane / metabolism*
  • Cell Membrane / pathology
  • Cyclic GMP
  • Endosomes / genetics
  • Endosomes / metabolism
  • Endosomes / pathology
  • Mice
  • Second Messenger Systems*
  • rab5 GTP-Binding Proteins / genetics
  • rab5 GTP-Binding Proteins / metabolism*

Substances

  • APP protein, mouse
  • Amyloid beta-Protein Precursor
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • Bace1 protein, mouse
  • rab5 GTP-Binding Proteins
  • Cyclic GMP