PT  - JOURNAL ARTICLE
AU  - Antonella Borreca
AU  - Francesco Valeri
AU  - Mariassunta De Luca
AU  - Lysianne Ernst
AU  - Arianna Russo
AU  - Alberto Cordella
AU  - Veronica Corsetti
AU  - Annalisa Nobili
AU  - Giusy Amadoro
AU  - Nicola Biagio Mercuri
AU  - Marcello D’Amelio
AU  - Martine Ammassari-Teule
TI  - Transient upregulation of translational efficiency in prodromal Tg2576 mice precipitates AD symptoms
AID  - 10.1101/581652
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 581652
4099  - http://biorxiv.org/content/early/2019/03/18/581652.short
4100  - http://biorxiv.org/content/early/2019/03/18/581652.full
AB  - 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 eIF2α (p-eIF2α), revealing a transient upregulation of overall translation. Differently, the reduction of hAPP mRNA polysomal signals was associated with increased p-eIF2α 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.eIF2αEukaryotic Initiation Factor 2BACE1Beta-secretase 1hAPPhuman amyloid precursor proteinFMRPFragile X Mental Retardation ProteinhnRNPCHeterogeneous Nuclear Ribonucleoprotein C (C1/C2)DMSODimethyl sulfoxideCASP-3caspase-3GDPGuanosin DiphosphateGTPGuanosine TiphosphateeIF4GEukaryotic translation initiation factor 4 GeIF4EEukaryotic translation initiation factor 4EDHPG