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.  Historically, HDAC inhibitor compounds with pro-synaptic effects have been plagued by known HDAC dose-limiting hematological toxicities, precluding their application to treating chronic neurologic conditions.  We identified a series of novel HDAC inhibitor compounds that selectively inhibit the HDAC-CoREST complex while minimizing hematological side effects.  HDAC1 and HDAC2 associate with multiple co-repressor complexes including CoREST, which regulates neuronal gene expression.  We show that selectively targeting the CoREST co-repressor complex results in increased 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 for multiple neurodegenerative diseases

2019 Fall National Meeting

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