The cyclic nucleotides (cNs) cAMP and cGMP are involved in the cellular mechanisms underlying long-term potentiation (LTP) and memory. Because a decrease of cNs is observed in aging and neurodegenerative disorders, including Alzheimer's Disease (AD), drugs restoring cNs levels, such as PDE inhibitors (PDE-Is), have been proposed as potential therapeutic strategies. Previous studies showed a crosstalk between cNs and amyloid-beta (Aβ), a peptide extensively known for its pathological role in AD but also implicated in the physiological processes of synaptic plasticity and memory.Based on these findings, here we evaluated the role of Aβ in cAMP- and cGMP-mediated cognitive functions. We used Amyloid Precursor Protein (APP)- knock out (KO) mice and alpha7 nicotinic acetylcholine receptor (α7)-KO mice to assess, respectively, whether the lack of Aβ production or the absence of its physiological receptor influenced the cNs-dependent enhancement of LTP and memory. We performed electrophysiological field recordings at CA3-CA1 hippocampal synapses and behavioral tests of Novel Object Recognition and Location.We found that treatments with roflumilast (PDE4-I) or vardenafil (PDE5-I), increasing cAMP or cGMP levels respectively, enhanced LTP and memory in 3-month-old wild type (WT) mice, but not in age-matched APP-KO and α7-KO mice. Similarly, chronic PDE4/5-I treatment failed to rescue the cognitive decline in aged APP-KO and α7-KO mice.In conclusion, our findings indicate that Aβ production and function are crucial for the cNs-mediated enhancement of synaptic plasticity and memory. These insights can help elucidate the mechanisms through which PDE-Is may improve cognition in aging and AD.