Amyloid precursor protein (APP) knock‐in mouse model recapitulates transciptomic signature in human late‐onset Alzheimer’s disease
Bibliographic record
Abstract
Abstract Background Over the years, improved rodent models have been generated aiming at recapitulating Alzheimer’s disease (AD) phenotype. However, the majority of these models harbor pathological mutations that are present in early‐onset AD, which represents only 5% of all cases. On the other hand, new models aiming at recapitulating late‐onset AD (LOAD) are of great interest. In this context, the knock‐in mouse model (hAβ‐KI line), in which murine amyloid precursor protein (APP) gene was humanized at the Aβ locus, was recently introduced as a potential LOAD model. Here, compare hippocampal transcriptomic profiles of human LOAD individuals and hAβ‐KI mouse model. We hypothesized that hippocampal transcriptomic profile of hAβ‐KI mouse model will be similar to the human LOAD. Method Publicly available human AD/cognitively unimpaired (CU) transcriptomic profiles of hippocampus were collected from GEO ( https://www.ncbi.nlm.nih.gov/geo/ ), merged and submitted to differential expression analysis and master regulator analysis (MRA) using R. RNAseq expression profile of hAβ‐KI mouse model was obtained at the AMP‐AD Knowledge Portal ( https://www.synapse.org/ ) and also submitted to differential expression analysis and MRA. Result We observed that the hippocampus of human LOAD individuals and hAβ‐KI mice model share over 100 differentially expressed genes (DEGs). Functional enrichment of Gene Ontology terms using these genes revealed several biological processes such as gliogenesis, glial cell differentiation, axon development and ensheathment of neurons. We also found shared transcription factors between human LOAD individuals and the hAβ‐KI mice model (Figure 1). Conclusion The novel hAβ‐KI mice, which expresses an humanized APP, has been proposed as a better model to mimic sporadic LOAD. Our early findings indicate that at the transcriptomic level the hAβ‐KI mice presents molecular alterations compatible to human LOAD condition. Thus, studies using this model may reveal important insights to understanding sporadic LOAD and lead to better translational concordance.
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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) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| 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) | 0.002 | 0.001 |
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".