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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

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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 1

The mature active form of ADAM10 is increased in HD mouse and human striatum.

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The mature active form of ADAM10 is increased in HD mouse and human stri...
(A) Representative Western blot for m-ADAM10 in the striata of WT (n = 4) and R6/2 mice (n = 5) at 8 weeks of age. (B) Quantification of data shown in A. *P < 0.05, unpaired t test. (C) Representative Western blot for m-ADAM10 in the striata of WT and heterozygous zQ175 mice at 25 and 54 weeks of age. (D) Quantification of data shown in C. 25 weeks: n = 6-9 mice/genotype; 54 weeks: n = 4 mice/genotype. *P < 0.05; ***P < 0.001, unpaired t test. (E) Representative Western blot of m-ADAM10 in the postmortem caudate of control (n = 5) and HD patients with Vonsattel grades 3 and 4 of neostriatal atrophy (n = 12). (F) Quantification of data shown in E. ***P < 0.001, nonparametric Mann-Whitney 2-tailed U test. α-Tubulin, loading control. Data are represented as mean ± SEM. Arrowheads, nonspecific bands.
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