Transient upregulation of translational efficiency in prodromal and early symptomatic Tg2576 mice contributes to Aβ pathology
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".