Project Summary Frontotemporal dementia (FTD) is a rare form of dementia that affects thousands of patients in the US and for which there is no cure. FTD usually manifests with changes in personality, behavior or mood, memory loss, confusion, and difficulty with day-to-day tasks. This symptomatology arises from neurodegeneration in the frontal and temporal lobes, which are areas of the brain that control personality, emotions, behavior, and some forms of cognition. One of the most common forms of FTD in the US is caused by mutations in Tau (sporadic and genetic) causing Tau intracellular accumulation and aggregation, synaptic dysfunction, neuronal death, and severe memory loss. Currently there are no US Food and Drug Administration (FDA) approved therapies for FTD, and there are no treatments that can stop or alter the course of disease progression. Therefore, there is an unmet need for the development of therapeutic strategies that can improve the quality of life of patients with FTD. We previously showed that the serine/threonine Protein kinase CK2 alpha prime (CK2α’) is a pathological sensor activated in the presence of protein aggregation and synaptic dysfunction in different human proteinopathies such as Huntington’s disease (HD) that contributes to neurodegeneration and behavioral alterations. Our previous and preliminary data demonstrated that some forms of FTD present similarities in the mechanisms that lead to neurodegeneration and behavioral deficits with HD. Our preliminary data removing one allele of CK2α’ in the FTD PS19 mouse model expressing a Tau mutation (P301L) associated with hereditary FTD restored the expression of glutamate related signaling (GRS) genes, increased soluble Tau levels and rescued memory deficits assessed in the Barnes maze task. These results represent a strong foundation for the pharmacological inhibition of CK2α’ as a potential therapeutic strategy for the treatment of neurodegeneration and memory decline associated with FTD. In this proposal we will investigate the therapeutic potential of the pharmacological inhibition of CK2α’ in the treatment of memory deficits associated with FTD using the FDA approved CK2 inhibitor Silmitasertib (CX4945). CX4945 is currently in clinical trials for the treatment of several cancers, is oral bioavailable and safe in humans, and if proven efficacious in the amelioration of memory loss in FTD mice it could become a potential therapeutic strategy for the treatment of FTD. We will treat two different groups of mice (pre-symptomatic and early symptomatic) and will evaluate the impact of CX4945 in learning and memory by conducting three different behavioral tasks (Y maze for spatial working memory, T-maze for spatial reference memory and Barnes maze for spatial learning and memory). We will conduct RNA-seq analyses in the FC of mice to assess the impact of CX4945 on GRS and other synaptic genes and its association with Tau/TauP levels and neuronal function using Ca2+ imaging an...