Targeting histonedemethylation to reverse age-relatedcognitive decline

The ability to learn and remember is essential for survival of all animal species. Fundamental questions remain about how memories are encoded and stored in the brain. The formation of long-term memories, also referred to as memory consolidation, requires new gene transcription and protein synthesis. As long-term memory is established or modified through gene expression changes, epigenetic mechanisms that regulategene transcription are likely to have key roles in memory consolidation. Furthermore, deficits in memory consolidation are thought to be the primary cause of age-related learning deficits. Thus, manipulating the epigenome may help prevent or even treat memory deficits in old age. Indeed, histone deacetylases have been successfully targeted to enhance learning in aged mice as well as various models of neurodegenerative diseases like Alzheimer's disease. Our recent preliminary analysis of mice with loss of KDM5B histone demethylase activity suggest a similar role for these enzymes, and therefore that targeting these enzymes might provide a novel way to treat age-related memory deficits.

Aim of the investigation:

The aim of this project will be to determine to what extent specific types of histone methylation areassociated with learning deficits associated with old age, if deletion or inhibition of KDM5B histone demethylase activity can restore these learning deficits and to screen for and develop more potent/specific KDM5B inhibitors for therapy.Specific objectives are:1)To determine if H3K4me3 induction is deficient in neurons of aged mice during learning.2)To determine if KDM5B deletion or inhibition can restore H3K4me3 and rescue age-related cognitive deficits.3)To screen for and/or develop more potent/specific/improved KDM5 inhibitors.