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 6

ADAM10 heterozygous deletion in the forebrain rescues synapse loss and cognitive decline in R6/2 mice.

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ADAM10 heterozygous deletion in the forebrain rescues synapse loss and c...
(A) CaMKIIα-Cre:Adam10Flox/+(A10cKO) mice were crossed with R6/2 mice to obtain R6/2:CaMKIIα-Cre:Adam10Flox/+(R6/2-A10cKO). (B) Representative Western blot for synaptic m-ADAM10 in the striata of WT, R6/2, and R6/2-A10cKO at 13 weeks of age. β-III Tubulin, loading control. Lanes were run on the same gel, but were noncontiguous. (C) Quantification of data in B. n = 3 mice/genotype, *P < 0.05, 1-way ANOVA with Bonferroni’s post hoc test. (D) Western blot of CTF N-CAD in the striata of WT, R6/2, and R6/2-A10cKO at 13 weeks of age. α-Tubulin, loading control. (E) Quantification of data in D. n = 3 mice/genotype. *P < 0.05; **P < 0.01, 1-way ANOVA with Bonferroni’s post hoc test. (F–I) Representative SBF-SEM segmentation and reconstruction of excitatory synapses (green) with their PSD (yellow) in 90 μm³ of striatum, and TEM images of striatal synaptic profile of WT (F), R6/2 (G), R6/2-A10cKO (H), and A10cKO (I) mice at 13 weeks of age. Scale bar: 100 nm. (J) Quantification of excitatory synapse density in 800 μm3 of striatal tissue/mouse in n = 3 mice/genotype. **P < 0.01; ***P < 0.001, 1-way ANOVA with Bonferroni’s post hoc test. (K) Quantification of SVs density and (L) docked vesicles/μm AZ in n = 3 mice/genotype. At least n = 60 excitatory synapses/genotype were analyzed. *P < 0.05; **P < 0.01; ***P < 0.001, 1-way ANOVA with nonparametric Dunn’s multiple comparison test. (M–P) Fear conditioning test on WT, R6/2, R6/2-A10cKO, and A10cKO mice at 9 and 13 weeks of age. n = 6–8 mice/genotype. (M, N) Contextual and cued fear responses evaluated as latency to freeze and (O, P) freezing time. *P < 0.05; **P < 0.01; ***P < 0.001, 1-way ANOVA with Newman-Keuls post hoc test. Data are represented as mean ± SEM.