TARGETING VNUT: NEW INSIGHTS INTO BIOMARKER DISCOVERY AND THERAPY IN ALZHEIMER’S DISEASE

The vesicular nucleotide transporter (VNUT) determines ATP storage and release at the synapse. Although ATP-mediated formation of extracellular adenosine sustaining the overfunction of adenosine A_2A receptors (A2AR) drives memory deficits in early Alzheimer’s disease (AD), the role of VNUT in AD remains unknown. We now aim to define the role of VNUT in physiological and AD conditions. The inhibition of VNUT with clodronate significantly altered synaptic transmission and plasticity in mouse hippocampal slices. Remarkably, clodronate exposure effectively prevented the impairment of LTP induced by Aβ1-42. In hippocampal synaptosomes from mice injected with Aβ1-42 (AD mice) we observed an increased ATP release, accompanied by an increase of VNUT immunoreactivity, an effect also observed in synaptosomes from hippocampal slices acutely exposed to Aβ1-42. Overall, these results point towards our hypothesis of a relationship between VNUT dysfunction and AD and suggest a potential for VNUT modulation against Aβ-induced synaptic deficits. Future studies will gauge the impact of silencing or genetically eliminating VNUT on behavior, electrophysiology and neurochemistry in the hippocampus of control or AD mice. We expect that, due to the ATP “dependence” of the CD73-A2AR tandem, and considering the positive results obtained with the blockade of either element of this pair in the prevention of AD-induced deficits, suppressing VNUT at neuronal synaptic terminals will reveal an impact on memory impairment, synaptic plasticity and on the extracellular dynamics of purines upon AD, thus defining VNUT as a novel biomarker and possible therapeutic target in this pathology. Work supported by FCT project 2023.13319.PEX.