O5‐06‐02: Elucidating the gene expression changes that underpin cholinergic dysfunction in a mouse model of Alzheimer's disease
Bibliographic record
Abstract
Cholinergic neurotransmission is impaired in Alzheimer's disease (AD) and loss of central cholinergic neurons is a key component of disease pathogenicity and symptomatology. Here we have performed translational profiling of cholinergic neurons of the TgCRND8 mouse model of AD to uncover the molecular underpinnings of this dysfunction. To profile actively translating mRNAs in cholinergic neurons of TgCRND8 mice, we applied the novel technique of Translating Ribosome Affinity Purification (TRAP). TRAP utilizes a bacterial artificial chromosome (bac) to generate transgenic mice expressing an eGFP-tagged ribosomal fusion protein, called eGFP-L10a, under the drive of the cholinergic neuron-specific choline acetyltransferase (ChAT) promoter. The ChAT-bac TRAP mice were crossed with TgCRND8 mice to generate double transgenic TgCRND8:ChAT-bacTRAP mice. High quality polysomal-bound mRNA (RIN>9) was isolated from the forebrain of TgCRND8:ChAT-bacTRAP mice and their littermate controls through use of the eGFP tag at 16- and 28-weeks of age (n=3 per group). In parallel, total RNA was also isolated from the forebrain of 28-week-old TgCRND8 (n=4) to facilitate a comparison of the cholinergic neuron translatome with the global transcriptome. Paired-end RNA-Seq followed by Tuxedo bioinformatics approaches revealed no striking changes in cholinergic neurons of 16-week-old TgCRND8:ChAT-bacTRAP mice compared to control littermates. In contrast, significant transcript expression changes were found in 28-week-old TgCRND8:ChAT-bacTRAP mice, with a significant down-regulation of cholinergic-specific markers (q<0.05). Moreover, the top KEGG pathway gene sets enriched in cholinergic neurons of the 28-week-old TgCRND8:ChAT-bacTRAP mice included axon guidance, calcium, Wnt and MAPK signaling, and AD (q<0.1). In contrast, the top KEGG pathway gene sets related to antigen processing and presentation, cytokine-cytokine receptor interaction, lysosome, and phagosome were enriched in the total mRNA compartment of TgCRND8 mice (q<0.1). Results of the differential gene expression analysis were validated by quantitative real-time polymerase chain reaction (p<0.05). Here we have used a novel molecular technique to uncover specific gene changes occurring in cholinergic neurons of a mouse model of AD. Generally, the neuron specific changes identified from TRAP were closely related to signalling pathways whereas the global expression changes from analysis of total RNA were more related to immune and inflammatory responses.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".