The PDE5 inhibitor vardenafil enhances glutamatergic transmission through amyloid-beta and cellular prion protein

: Memory and synaptic plasticity are regulated by cyclic guanosine monophosphate (cGMP) signaling. Phosphodiesterase 5 (PDE5) inhibitors, such as vardenafil (VDF), elevate intracellular cGMP levels and represent potential therapeutics for cognitive disorders, including Alzheimer's disease (AD). However, the signaling pathways linking PDE5 inhibition to excitatory synaptic transmission remain incompletely defined. In particular, whether PDE5 inhibition engages amyloid-β (Aβ)-dependent mechanisms to regulate glutamatergic synapses remains unclear. Using biochemical, immunocytochemical, and electrophysiological approaches in neuronal systems, we show that VDF activates an Aβ-cellular prion protein (PrPC)-dependent pathway that enhances presynaptic glutamatergic function. Specifically, VDF increases Aβ levels, leading to a marked reduction in PrPC surface exposure, an effect prevented by blocking Aβ production. We further demonstrate that PrPC facilitates Aβ internalization, supporting a dynamic coupling between Aβ and PrPC trafficking. Functionally, VDF selectively augments presynaptic excitatory transmission, as indicated by increased VGLUT1 puncta density and elevated miniature excitatory postsynaptic current (mEPSC) frequency, without changes in mEPSC amplitude. Disrupting Aβ-PrPC interaction abolishes these presynaptic effects, establishing this axis as a required mediator of the synaptic response to VDF. Together, these findings identify a functional link between PDE5 inhibition and Aβ-PrPC-dependent modulation of presynaptic glutamatergic transmission, expanding the framework of Aβ-PrPC signaling beyond neurotoxicity and highlighting its context-dependent role in synaptic regulation.