Inhibition of ADAM10 has therapeutic potential in Huntington disease (HD), say researchers. Vezzoli et al. found that striatal levels of the mature active form of ADAM10 were increased in patients with HD and mouse models of the condition. Using a mouse model and post-mortem caudate tissue from patients with HD, the researchers demonstrated that mature ADAM10 accumulated at the synapse, leading to increased proteolysis of N-cadherin, which resulted in compromised adhesion between the presynaptic and postsynaptic membrane. The researchers showed that allele-specific downregulation of mutant huntingtin protein could prevent the increases in mature ADAM10 levels and N-cadherin proteolysis. Further experiments showed that administration of an ADAM10 inhibitor improved the functional defects at the synapse in HD mouse models, and that heterozygous deletion of ADAM10 in the forebrain prevented synapse loss and synaptic ultrastructural defects in the striatum of HD mice, thereby reducing cognitive impairment.