ArticleThe Journal of clinical investigation2019
Inhibiting pathologically active ADAM10 rescues synaptic and cognitive decline in Huntington's disease.
Article in The Journal of clinical investigation, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers, 2 of them syntheses that pooled it.
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Who cites it
32 citing papers in PubMed, 2 syntheses or guidelines pooled it, 99 citations in OpenAlex.
- Chronic cholesterol administration to the brain supports complete and long-lasting cognitive and motor amelioration in Huntington's disease.Pharmacological research · 2023Pooled it
- Cationic Arginine-Rich Peptides (CARPs): A Novel Class of Neuroprotective Agents With a Multimodal Mechanism of Action.Frontiers in neurology · 2020Pooled it
- Huntingtin and its allies at the cortico-striatal synapse.Cell death & disease · 2026Review
- Synaptic aging and neurodegeneration: the role of synaptic vesicle dynamics and neurotransmitter imbalance.Biogerontology · 2026Review
- Review
- Review
- Therapeutic approaches targeting aging and cellular senescence in Huntington's disease.CNS neuroscience & therapeutics · 2024Review
- Non-canonical function of ADAM10 in presynaptic plasticity.Cellular and molecular life sciences : CMLS · 2024Article
- Neuroprotection by ADAM10 inhibition requires TrkB signaling in the Huntington's disease hippocampus.Cellular and molecular life sciences : CMLS · 2024Article
- Huntington's disease cellular phenotypes are rescued non-cell autonomously by healthy cells in mosaic telencephalic organoids.Nature communications · 2024Article
- A delay in vesicle endocytosis by a C-terminal fragment of N-cadherin enhances Aβ synaptotoxicity.Cell death discovery · 2023Article
- Microglia and complement mediate early corticostriatal synapse loss and cognitive dysfunction in Huntington's disease.Nature medicine · 2023Article
- IKBKB reduces huntingtin aggregation by phosphorylating serine 13 via a non-canonical IKK pathway.Life science alliance · 2023Article
- Brain-Derived Neurotrophic Factor Dysregulation as an Essential Pathological Feature in Huntington's Disease: Mechanisms and Potential Therapeutics.Biomedicines · 2023Review
- Novel therapeutic approaches to target neurodegeneration.British journal of pharmacology · 2023Review
- Prenatal DEHP exposure predicts neurological disorders via transgenerational epigenetics.Scientific reports · 2023Article
- MAP4K4 promotes ovarian cancer metastasis through diminishing ADAM10-dependent N-cadherin cleavage.Oncogene · 2023Article
- Age-Dependent Dysregulation of APP in Neuronal and Skin Cells from Fragile X Individuals.Cells · 2023Article
- The Autism Spectrum Disorder-Associated Bacterial MetaboliteInternational journal of molecular sciences · 2022Article
- The development of ADAM10 endocytosis inhibitors for the treatment of Alzheimer's disease.Molecular therapy : the journal of the American Society of Gene Therapy · 2022Article
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Authors and funding
23 authors at 7 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.