Synaptic dysfunction is a pathological feature in many neurodegenerative disorders, including Alzheimer’s disease, and synaptic loss correlates closely with cognitive decline. Histone deacetylase enzymes (HDACs) are involved in chromatin remodeling and gene expression, and have been shown to regulate synaptogenesis and synaptic plasticity, thus providing an attractive drug discovery target for promoting synaptic growth and function. HDAC1 and HDAC2 associate with multiple co-repressor complexes including CoREST, which regulates the expression of many neuronal genes. We have identified a series of novel HDAC inhibitor compounds that selectively inhibit the HDAC-CoREST complex, resulting in increases in dendritic spine density and synaptic proteins, and improved long term potentiation in a mouse model at doses which provide a substantial safety margin that would enable chronic treatment. This approach represents a promising therapeutic strategy in targeting synaptic pathology involved in multiple neurologic disorders.

CoREST complex-selective HDAC inhibitors promote pro-synaptic effects and represent promising therapies to treat synaptopathies

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.