Targeting Tet2 to Enhance Cognition: Manipulating the Methylome as a Potential Treatment for Alzheimer’s Disease

Every seven seconds an individual is diagnosed with dementia, 80% of which being specifically caused by/characterized as Alzheimer’s disease (AD). More than three million Americans are diagnosed with some form of dementia every year, and the World Health Organization estimates that there will be 75.6 million cases world-wide by 2030. Currently, there is no effective treatment, no means to halt the progression of the disease, and dementia is always fatal. It is known that learning generates an epigenetic reorganization in the brain that facilitates long term memory. One of these epigenetic marks is DNA methylation which is required for the formation of new memories. Levels of DNA methylation in the hippocampus are regulated via the Ten-Eleven Translocase (TET) family of enzymes which oxidize and remove methyl marks at the five position of cytosine. In this study, we utilized a series of Tet2 knockout mice (Tet2- selective ASO and Tet2 floxed mice) to determine the role that TET2 plays in the formation and storage/maintenance of memories. A significant increase in performance in an object location memory task (24 hour-LTM and 7 day-remote) in Tet2 ASO KO and CaMKIIα-Cre KD mice compared to WT mice was observed. This suggests that the increased fidelity of methyl marks in the hippocampus in response to downregulating Tet2 prior to learning may increase the lifetime of the new memory. This work furthers our understanding of the involvement of Tet2 in memory formation and maintenance and will allows us to assess the potential of TET2 as a future therapeutic target for the treatment of diseases and disorders of memory such as AD