Cell-type-specific mechanisms implicated in mRNA translation and memory in Alzheimer's disease

mRNA translation in the brain is necessary for long-term memory consolidation, and its dysregulation is implicated in memory loss in Alzheimer’s disease. Pathological features of Alzheimer’s disease include the accumulation of amyloid-beta peptides and hyperphosphorylated tau proteins. The accumulation of these proteins results in many stressors that trigger the integrated stress response, which phosphorylates the α subunit of eukaryotic initiation factor 2 (p-eIF2α), inhibiting general protein synthesis. Prolonged integrated stress response activation in Alzheimer’s disease increases p-eIF2α levels, downregulates general protein synthesis, and impairs long-term memory consolidation. p-eIF2α is a key translational control mechanism to bidirectionally control long-term memory in health and disease. Learning stimulates general protein synthesis in a healthy brain by dephosphorylation of p-eIF2α. Cell-type-specific suppression of the integrated stress response in mice models of translation rescued memory deficit. However, the cell-type-specific translation regulation mechanisms are less understood in Alzheimer’s disease. Our objectives are to identify the cell-types with dysregulated mRNA translation in Alzheimer's disease and to restore translation in those cell-types to assess there effects on memory in Alzheimer's disease. To this end, Alzheimer's disease mice will be immuno-stained for p-eIF2α and eIF2α in specific cell-types, and eIF2α will be knocked-in to suppress the integrated stress response. Thus far, we introduced knocked-in eIF2α into the Alzheimer’s disease mice astrocytes and observed that stimulating translation in astrocytes can rescue memory deficits. Dissecting cell-type-specific translational control mechanisms in Alzheimer’s can aid in developing therapeutics to target specific cell populations, potentially leading to better treatment outcomes for Alzheimer’s disease.