Long-term potentiation (LTP) and the process of memory formation require activation of cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) pathways. Notably, recent evidence indicated that both cyclic nucleotides boost the production of amyloid-beta (Aβ) peptides. In particular, cAMP was shown to favor hippocampal LTP by stimulating the synthesis of the amyloid precursor protein APP, whereas cGMP was found to enhance LTP and to improve memory by increasing Aβ levels without affecting the expression of APP. The results of the present study substantiate that cGMP has a role in the endocytic pathway of APP and suggest a scenario where the cyclic nucleotide enhances the production of Aβ by favoring the trafficking of APP from the cell cortex to the endolysosomal compartment.