I023 Evaluating the impact of ADAM10 pharmacological inhibition on cortico-striatal dysfunction in Huntington’s disease
Year: 2024
Type: conference-abstract
Abstract: Background 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. Aim Our aim is to evaluate whether the ADAM10 inhibitor GI254023X alleviates pre- and postsynaptic defects in the HD cortico-striatal circuitry. Methods 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. Results 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. Conclusion 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)
Institutions: University of Milan, Istituto Nazionale Genetica Molecolare
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W4402373714