Transient upregulation of translational efficiency in prodromal and early symptomatic Tg2576 mice contributes to Aβ pathology

NEUROBIOLOGY OF DISEASE

卷:139

Article

Borreca, Antonella^1,2  Valeri, Francesco³  De Luca, Mariassunta³  Ernst, Lysianne⁴  Russo, Arianna⁵  Nobili, Annalisa^3,6  Cordella, Alberto^3,6  Corsetti, Veronica⁷  Amadoro, Giuseppina^7,8  Mercuri, Nicola Biagio^3,9  D'Amelio, Marcello^3,6  Ammassari-Teule, Martine^3,10 

[1] Natl Res Council CNR, Inst Neurosci, Via Vanvitelli 32, I-20129 Milan, Italy

[2] Humanitas Univ, Dept Biomed Sci, Via Rita Levi Montalcini 4, I-20090 Pieve Emanuele Milan, Italy

[3] IRCCS Fdn Santa Lucia, Ctr Europeo Ric Cervello CERC, Via Fosso di Fiorano 64, I-00143 Rome, Italy

[4] Univ Namur, Fac Sci, Namur, Belgium

[5] INGM Natl Inst Mol Genet, Via Francesco Sforza 35, I-20122 Milan, Italy

[6] Univ Campus Biomed, Dept Med, Unit Mol Neurosci, Via Alvaro del Portillo 21, I-00128 Rome, Italy

[7] EBRI Fdn, Viale Regina Elena 295, Rome, Italy

[8] IFT CNR, Via Fosso del Cavaliere 100, I-00133 Rome, Italy

[9] Univ Roma Tor Vergata, I-00133 Rome, Italy

[10] CNR, Inst Biochem & Cellular Biol IBBC, Via Ercole Ramarini 32, I-00015 Rome, Italy

关键词: Alzheimer's disease;    Tg2576 mice;    hAPP mRNA;    eIF2 alpha;    Translational control;    Salubrinal;    Pre-symptomatic markers;    Cognition;    Synaptic plasticity;   

DOI  :  10.1016/j.nbd.2020.104787

来源: Elsevier

【 摘 要 】

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 eIF2 alpha (p-eIF2 alpha) 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, A beta species, 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.