A33 ADAM10 in Huntington's disease synaptic dysfunctions. (12th September 2022)

• Record Type: Journal Article
• Authors: Vezzoli, Elena; Scolz, Andrea; Villa, Michela; Cattaneo, Elena; Zuccato, Chiara
• Is Part Of: Journal of neurology, neurosurgery and psychiatry. Volume 93(2022)Supplement 1
• Page Start: A12
• Page End: A12
• Publication Date: 2022-09-12
• Subjects: ADAM10 -- synapse -- Huntington' Disease; Neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; Psychiatry -- Periodicals; 616.8
• DOI: 10.1136/jnnp-2022-ehdn.33
• Languages: English
• ISSNs: 0022-3050

Abstract

Abstract : Background: A disintegrin and metalloproteinase 10 (ADAM10) is a constitutive alpha-secretase found at the excitatory synapse and implicated in the molecular structure and function of adult neuronal circuitries. Recently, we described that active ADAM10 increases at the synapse in Huntington's Disease (HD) striatum and cortex and impairs both the pre-synapse (through reduced synaptic vesicle density) and the post-synapse (by proteolysis of synaptic cell adhesion protein Ncadherin). Normalization of the active ADAM10 level restores synaptic impairments and prevents cognitive and memory decline in HD mice. Recent findings suggest that these manifestations, which historically have been linked to cortico-striatal circuitry failure, are also caused by hippocampal dysfunctions. In fact, long-term potentiation (LTP) is substantially hampered in the HD hippocampus, which also shows synapse loss. Aim: The aim of this study is to investigate the ADAM10 pathway in the hippocampus of HD mice and its contribution to dendritic spine loss observed in this brain area. Methods: Synapse morphology is studied by Golgi staining and by Transmission Electron Microscopy (TEM) in combination with genetic strategies to manipulate ADAM10 level in vivo in the HD brain. Results: Preliminary investigations of the synapse morphology indicate that an increase in active ADAM10 contributes to synaptic abnormalities in the hippocampus of a mouse model of HD. Conclusions: Our study validates ADAM10's involvement in HD synaptic dysfunctions and its inhibition as a neuroprotective therapy for the disease.