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cGMP favors the interaction between APP and BACE1 by inhibiting Rab5 GTPase activity.
- Source :
-
Scientific reports [Sci Rep] 2020 Jan 28; Vol. 10 (1), pp. 1358. Date of Electronic Publication: 2020 Jan 28. - Publication Year :
- 2020
-
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.
- Subjects :
- Alzheimer Disease genetics
Alzheimer Disease pathology
Amyloid Precursor Protein Secretases genetics
Amyloid beta-Protein Precursor genetics
Animals
Aspartic Acid Endopeptidases genetics
Cell Line
Cell Membrane genetics
Cell Membrane pathology
Cyclic GMP
Endosomes genetics
Endosomes metabolism
Endosomes pathology
Mice
rab5 GTP-Binding Proteins genetics
Alzheimer Disease metabolism
Amyloid Precursor Protein Secretases metabolism
Amyloid beta-Protein Precursor metabolism
Aspartic Acid Endopeptidases metabolism
Cell Membrane metabolism
Second Messenger Systems
rab5 GTP-Binding Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2045-2322
- Volume :
- 10
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Scientific reports
- Publication Type :
- Academic Journal
- Accession number :
- 31992816
- Full Text :
- https://doi.org/10.1038/s41598-020-58476-8