I023 Evaluating the impact of ADAM10 pharmacological inhibition on cortico-striatal dysfunction in Huntington’s disease

<h3>Background</h3> Cortico-striatal dysfunction is an early pathogenic event contributing to cognitive decline in Huntington’s disease (HD). A Disintegrin and Metalloproteinase Domain-Containing Protein 10 (ADAM10) is enriched in the brain and governs excitatory synapse structure and function by shedding neuronal trans-synaptic proteins. We have previously linked ADAM10 hyperactivity and enhanced proteolysis of N-Cadherin to HD synaptic dysfunction and cognitive decline. <h3>Aim</h3> Our aim is to evaluate whether the ADAM10 inhibitor GI254023X alleviates pre- and postsynaptic defects in the HD cortico-striatal circuitry. <h3>Methods</h3> A two-compartment microfluidic system was used, together with mouse primary cortical and striatal neurons from wild-type and HD mice, to reconstruct the cortico-striatal circuitry in vitro. Immunolabelling of pre- and post-synaptic proteins was used to identify excitatory synaptic contacts. Furthermore, live-imaging microscopy was employed to monitor Brain-Derived Neurotrophic Factor (BDNF) transport. Cortical and striatal neurons were exposed to GI254023X in acute and chronic paradigms. <h3>Results</h3> We recreated the wild-type and HD cortico-striatal circuitry in microfluidic chambers. We developed an automated pipeline to quantitatively evaluate excitatory synapse density. We set up conditions to study transport dynamics of BDNF-containing vesicles in the cortical afferents. We identified GI254023X doses and exposure times that conferred neuroprotection to HD neurons. Currently, we are testing if GI254023X restores BDNF transport in HD cortical neurons. <h3>Conclusion</h3> Our findings suggest that pharmacological inhibition of ADAM10 attenuates synaptic phenotypes in the HD cortico-striatal circuitry. Future studies will evaluate the therapeutic potential of GI254023X in rescuing synaptic and cognitive abnormalities in HD mice. Funded by Telethon Foundation (#GGP20067)