Supplement to R01AG073823 PI: Ma Abstract This project for the R01 proposal focuses on elucidation of the molecular mechanisms underlying aging-related cognitive impairments in Down syndrome (DS). The central hypothesis to be tested for the main R01 grant is that upregulation of the capacity for de novo protein synthesis, via suppression of eEF2K and eEF2 phosphorylation, will improve multiple aging-related pathophysiology in DS including synaptic failure and cognitive deficits. A key rationale for the project is based on our findings that levels of eEF2K phosphorylation are abnormally high in brain tissue from both DS patients and DS mouse models. For this supplement, we propose to investigate, within the scope of the currently funded R01 grant (AG073823, PI: Ma), the effects of neuronal eEF2K overexpression on synaptic and cognitive function by taking advantage of a novel transgenic mouse model (eEF2K cKI) that we have recently generated.