Inhibiting pathologically active ADAM10 rescues synaptic and cognitive decline in Huntington’s disease
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
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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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 5

TAT-Pro-ADAM10709–729 peptide normalizes N-CAD proteolysis and rescues cognitive deficits in R6/2 mice.

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TAT-Pro-ADAM10709–729 peptide normalizes N-CAD proteolysis and rescues c...
(A) TAT-Pro-ADAM10709–729 (TAT-Pro) interferes with ADAM10/SAP97 interaction and impairs ADAM10 synaptic trafficking. TAT-Ala-ADAM10709–729 (TAT-Ala), inactive peptide. 12-week-old WT and R6/2 mice received 2 i.p. injections of TAT-Pro or TAT-Ala at 2 nmol/g 24 hours apart. Saline solution, vehicle. Synaptic level of m-ADAM10, N-CAD proteolysis, and cognitive function were monitored 24 hours after the second i.p. injection. (B) Representative Western blot for m-ADAM10 in striatal synaptic fractions of 12-week-old WT and R6/2 mice treated with TAT-Pro or TAT-Ala. β-III Tubulin, loading control. Arrowhead, nonspecific band. Lanes were run on the same gel, but were noncontiguous. (C) Quantification of data in B. WT-TAT-Ala, n = 4; R6/2-TAT-Ala, n = 5; R6/2-TAT-Pro, n = 6. *P < 0.05; **P < 0.01, 1-way ANOVA with Bonferroni’s post hoc test. (D) Representative Western blot showing effects of TAT peptides on N-CAD proteolysis in the striata of R6/2 mice. α-Tubulin, loading control. (E) Quantification of data in D. WT-saline, n = 3; WT-TAT-Ala, n = 3; R6/2-saline, n = 3; R6/2-TAT-Ala, n = 6; R6/2-TAT-Pro, n = 6. *P < 0.05; **P < 0.01; ***P < 0.001, 1-way ANOVA with Bonferroni’s post hoc test. (F) Representative Western blot showing effects of TAT peptides on N-CAD proteolysis in the cortices of R6/2 mice. α-Tubulin, loading control. (G) Quantification of data shown in F. WT-saline, n = 4; WT-TAT-Ala, n = 3; R6/2-saline, n = 3; R6/2-TAT-Ala, n = 4; R6/2-TAT-Pro, n = 4. *P < 0.05; **P < 0.01, 1-way ANOVA with Bonferroni’s post hoc test. (H, I) Effect of TAT peptides in the fear conditioning test in WT and R6/2 mice at 12 weeks of age. WT-TAT-Ala, n = 9; R6/2-TAT-Ala, n = 8; R6/2-TAT-Pro, n = 8. Cued fear response evaluated as latency to freeze (H) and freezing time (I). *P < 0.05; **P < 0.01, 1-way ANOVA with Newman-Keuls. Data are represented as mean ± SEM.