PROJECT SUMMARY/ABSTRACT Extensive studies have demonstrated that cellular stress and the subsequent stress response, such as global translational suppression, are exaggerated in amyloid beta (Aβ)–associated Alzheimer’s disease and that they facilitate neurodegeneration. Alleviating the stress response has been shown to improve neuronal and circuit functions in animal models of Aβ pathology. However, our understanding of the molecular mechanisms underlying Aβ-induced cellular stress response is limited. Furthermore, it is also unclear whether there is any sex-specific regulation behind those mechanisms. To address these questions, we have gathered preliminary data that reveal an Aβ-induced up-regulation of fragile X mental retardation protein (FMRP) and the FMRP- dependent phosphorylation of eukaryotic translation elongation factor 2 (eEF2) and subsequent translational suppression. Remarkably, our data also suggest that these mechanisms potentially occur only in female but not in male mice in an Aβ-pathology mouse model. We therefore hypothesize that elevated FMRP induced by Aβ contributes to exaggerated translational suppression and neurodegeneration, particularly in females. In Aim 1, we propose to characterize, as well as reduce, Aβ-associated eEF2 phosphorylation to ameliorate translational suppression in primary neurons in vitro. In Aim 2, we propose to study sex-specific regulation of FMRP and translational suppression in Aβ pathology in vivo. We also propose to genetically inhibit FMRP to ameliorate Aβ- induced neurodegeneration in mice in vivo. This supplemental research is within the scope of the Aim 3 of the parent award in which the FMRP-dependent regulation of global translational suppression and synaptic plasticity are being studied through phosphorylation signaling. Through the research of FMRP in Alzheimer’s disease, we expect that our results will (1) elucidate a novel mechanism by which accumulation of Aβ leads to translational suppression, (2) uncover a sex-specific regulation in translational suppression in Aβ pathology, and (3) suggest novel therapeutic targets for ameliorating exaggerated cellular stress response and neurodegeneration in Alzheimer’s disease. Building on existing tools and substantial knowledge of FMRP, our research has the potential to quickly open new avenues for the future study of Alzheimer’s disease–associated cognitive decline and memory impairment.