Inhibiting pathologically active ADAM10 rescues synaptic and cognitive decline in Huntington’s disease
Elena Vezzoli, … , Elena Cattaneo, Chiara Zuccato
Elena Vezzoli, … , Elena Cattaneo, Chiara Zuccato
Published May 6, 2019
Citation Information: J Clin Invest. 2019;129(6):2390-2403. https://doi.org/10.1172/JCI120616.
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Research Article Neuroscience

Inhibiting pathologically active ADAM10 rescues synaptic and cognitive decline in Huntington’s disease

Abstract

A disintegrine and metalloproteinase 10 (ADAM10) is implicated in synaptic function through its interaction with postsynaptic receptors and adhesion molecules. Here, we report that levels of active ADAM10 are increased in Huntington’s disease (HD) mouse cortices and striata and in human postmortem caudate. We show that, in the presence of polyglutamine-expanded (polyQ-expanded) huntingtin (HTT), ADAM10 accumulates at the postsynaptic densities (PSDs) and causes excessive cleavage of the synaptic protein N-cadherin (N-CAD). This aberrant phenotype is also detected in neurons from HD patients where it can be reverted by selective silencing of mutant HTT. Consistently, ex vivo delivery of an ADAM10 synthetic inhibitor reduces N-CAD proteolysis and corrects electrophysiological alterations in striatal medium-sized spiny neurons (MSNs) of 2 HD mouse models. Moreover, we show that heterozygous conditional deletion of ADAM10 or delivery of a competitive TAT-Pro-ADAM10709–729 peptide in R6/2 mice prevents N-CAD proteolysis and ameliorates cognitive deficits in the mice. Reduction in synapse loss was also found in R6/2 mice conditionally deleted for ADAM10. Taken together, these results point to a detrimental role of hyperactive ADAM10 at the HD synapse and provide preclinical evidence of the therapeutic potential of ADAM10 inhibition in HD.

Authors

Elena Vezzoli, Ilaria Caron, Francesca Talpo, Dario Besusso, Paola Conforti, Elisa Battaglia, Elisa Sogne, Andrea Falqui, Lara Petricca, Margherita Verani, Paola Martufi, Andrea Caricasole, Alberto Bresciani, Ottavia Cecchetti, Pia Rivetti di Val Cervo, Giulio Sancini, Olaf Riess, Hoa Nguyen, Lisa Seipold, Paul Saftig, Gerardo Biella, Elena Cattaneo, Chiara Zuccato

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Figure 4

Treatment with the ADAM10 inhibitor GI254023X reduces N-CAD proteolysis and rescues electrophysiological defects of the excitatory synapse in HD.

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Treatment with the ADAM10 inhibitor GI254023X reduces N-CAD proteolysis ...
(A) Representative Western blot for N-CAD on corticostriatal brain slices from 4 untreated 11-week-old WT mice and 1 R6/2 mouse acutely treated with vehicle and GI254023X at concentrations of 1, 10, 100, and 1000 nM. α-Tubulin, loading control. (B) Quantification of data shown in A. WT, n = 8; R6/2 treated with GI254023X or vehicle, n = 3–5. ***P < 0.001, 1-way ANOVA with Bonferroni’s post hoc test. (C) sEPSCs frequencies recorded from striatal MSNs of WT and R6/2 mice at 11 weeks of age. WT, n = 17; R6/2-untreated, n = 15; R6/2-GI254023X-50nM, n = 16. **P < 0.01; ***P < 0.001, 1-way ANOVA with Bonferroni’s post hoc test. (D) sEPSC frequencies recorded from striatal MSNs of WT and zQ175 mice at 54 weeks of age. WT, n = 7; zQ175-untreated, n = 7; zQ175-GI254023X-50nM, n = 7. *P < 0.05; *** P < 0.001, 1-way ANOVA with Bonferroni’s post hoc test. (E) mEPSC frequencies recorded from striatal MSNs of WT and R6/2 mice at 11 weeks of age. WT, n = 7; R6/2-untreated, n = 7; and R6/2-GI254023X-50nM, n = 8. *P < 0.05; ***P < 0.001, 1-way ANOVA with Bonferroni’s post hoc test. Data are represented as mean ± SEM.