Transient upregulation of translational efficiency in prodromal and early symptomatic Tg2576 mice contributes to Aβ pathology.
TG2576 mice show highest levels of the full length mutant Swedish Human Amyloid Precursor Protein (APPKM670/671LN) during prodromal and early sympotomatic stages. Interestingly, this occurs in association with the unbalanced expression of two of its RNA Binding proteins (RBPs) opposite regulators, the Fragile-X Mental Retardation Protein (FMRP) and the heteronuclear Ribonucleoprotein C (hnRNP C). Whether an augmentation in overall translational efficiency also contributes to the elevation of APP levels at those early developmental stages is currently unknown. We investigated this possibility by performing a longitudinal polyribosome profiling analysis of APP mRNA and protein in total hippocampal extracts from Tg2576 mice. Results showed that protein polysomal signals were exclusively detected in pre-symptomatic (1 months) and early symptomatic (3 months) mutant mice. Differently, hAPP mRNA polysomal signals were detected at any age, but a peak of expression was found when mice were 3-month old. Consistent with an early but transient rise of translational efficiency, the phosphorylated form of the initial translation factor eIF2α (p-eIF2α) was reduced at pre-symptomatic and early symptomatic stages, whereas it was increased at the fully symptomatic stage. Pharmacological downregulation of overall translation in early symptomatic mutants was then found to reduce hippocampal levels of full length APP, Aβspecies, BACE1 and Caspase-3, to rescue predominant LTD at hippocampal synapses, to revert dendritic spine loss and memory alterations, and to reinstate memory-induced c-fosactivation. Altogether, our findings demonstrate that overall translation is upregulated in prodromal and early symptomatic Tg2576 mice, and that restoring proper translational control at the onset of AD-like symptoms blocks the emergence of the AD-like phenotype.
['Borreca|Antonella|A|', 'Valeri|Francesco|F|', 'De Luca|Mariassunta|M|', 'Ernst|Lysianne|L|', 'Russo|Arianna|A|', 'Nobili|Annalisa|A|', 'Cordella|Alberto|A|', 'Corsetti|Veronica|V|', 'Amadoro|Giuseppina|G|', 'Mercuri|Nicola Biagio|NB|', "D'Amelio|Marcello|M|", 'Ammassari-Teule|Martine|M|']
D000544:Alzheimer Disease D053829:Amyloid Precursor Protein Secretases D016229:Amyloid beta-Peptides D016564:Amyloid beta-Protein Precursor D000818:Animals D004195:Disease Models, Animal D015852:Eukaryotic Initiation Factor-2 D005260:Female D051860:Fragile X Mental Retardation Protein D006624:Hippocampus D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D008822:Mice, Transgenic D009474:Neurons D010766:Phosphorylation D062706:Prodromal Symptoms D012333:RNA, Messenger D013569:Synapses D015854:Up-Regulation
Tg2576 mice hAPP mRNA eIF2α Translational control Alzheimer's disease Cognition Pre-symptomatic markers Salubrinal Synaptic plasticity