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.
Highlights
We previously demonstrated that cyclic guanosine monophosphate stimulates amyloid precursor protein (APP) and beta-secretase (BACE1) approximation in neuronal endo-lysosomal compartments, boosting the production of amyloid-β (Aβ) peptides and enhancing synaptic plasticity and memory
Our previous reports demonstrated that the enhancement of cyclic guanosine monophosphate in neuronal microdomains triggers the internalization of APP and the APP-BACE1 interaction in early endosomal compartments[11,12]
We further characterized the trafficking of APP and BACE1 under cyclic guanosine monophosphate (cGMP) stimulation, finding that the cyclic nucleotide inhibits the activity of Rab[5] by lowering its GTP-bound conformation
Summary
We previously demonstrated that cyclic guanosine monophosphate (cGMP) stimulates amyloid precursor protein (APP) and beta-secretase (BACE1) approximation in neuronal endo-lysosomal compartments, boosting the production of amyloid-β (Aβ) peptides and enhancing synaptic plasticity and memory. We found that expression of a dominant-negative Rab[5] mutant increases both APP-BACE1 approximation and Aβ extracellular levels, mimicking the effects induced by cGMP. These results reveal a functional correlation between the cGMP/Aβ pathway and the activity of Rab[5] that may contribute to the understanding of Alzheimer’s disease pathophysiology. Our previous reports demonstrated that the enhancement of cyclic guanosine monophosphate (cGMP) in neuronal microdomains triggers the internalization of APP and the APP-BACE1 interaction in early endosomal compartments[11,12] This effect induced the production of Aβ peptides, which was instrumental to sustain hippocampal long-term potentiation and memory formation[12]. Overactivation of Rab[5] has been shown to cause endosome enlargement, one of the earliest pathological alterations observed in the brain of AD and Down syndrome patients[13], whereas expression of a dominant-negative Rab[5] mutant was found to reverse neuronal atrophy in Drosophila[14]
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