Transient upregulation of translational efficiency in prodromal Tg2576 mice precipitates AD symptoms

Tg2576 mice overexpressing APPK670/671L exhibit elevated hAPP levels from birth but remain at a prodromal stage until 3 months of age. Whether variations in hAPP mRNA specific and overall translation occur during development and precipitates the transition from an asymptomatic to a symptomatic stage is unknown. By performing polysome profiling and distribution of hAPP, and measuring the levels of eukaryotic initial translation factors in hippocampal extracts from pre- and early symptomatic Tg2576 mice, we found that the presence of mRNA and protein polysomal signals was associated with decreased levels of the phosphorylated form of the initial translation factor eIF2a (p-eIF2a), revealing a transient upregulation of overall translation. Differently, the reduction of hAPP mRNA polysomal signals was associated with increased p-eIF2a levels - repressing translation - when mice were symptomatic, suggesting a compensatory mechanism aimed at downregulating hAPP mRNA. Confirming that prodromal upregulation of translational efficiency contributes to AD pathogenesis, pharmacological restoration of proper translational control in early symptomatic mice blocked the manifestation of neural and cognitive AD-like alterations.