Transcriptomic profiling of glutamatergic gliotransmission‐specialized astrocytes in Alzheimer's disease mouse models
Bibliographic record
Abstract
BACKGROUND: Astrocytes, the most abundant glial cells in the brain, exhibit remarkable heterogeneity and play critical roles in maintaining brain homeostasis. Their responses to Alzheimer's disease (AD) pathology are diverse, particularly in the context of glutamate excitotoxicity - a hallmark of AD characterized by impaired astrocytic glutamate uptake. Recently, de Ceglia et al. (2023) identified a astrocyte subtype involved in glutamatergic gliotransmission, defined by the expression of genes linked to glutamate exocytosis. Here we investigate whether the transcriptional profile of this specific astrocyte subtype is altered across various AD mouse models. METHOD: We conducted differential gene expression analysis and cellular deconvolution using population-specific expression analysis (PSEA) on bulk RNA-seq data from the hippocampus of three amyloidosis models: APP/PS1 (n = 18), 5xFAD (n = 49), and hAβKi (n = 41). Cell type-specific gene expression signatures for astrocytes, neurons, oligodendrocytes, endothelial cells, and microglia were assigned using the BRETIGEA R package. The transcriptional signature for glutamatergic gliotransmission-specialized astrocytes consisted of 15 genes associated with synaptic-like glutamate release machinery. We analyzed cellular enrichment proportions and identified differentially expressed genes (DEGs) within the glutamatergic astrocyte signature across the three models (p < 0.05). RESULT: The APP/PS1 model showed the highest glutamatergic astrocyte enrichment (24.8%), similar to hAβKI (23.8%), while 5xFAD had minimal enrichment (2.2%) (Figure 1). From these astrocytic genes, DEGs analysis revealed 52 upregulated and 547 downregulated genes in the APP/PS1 model, 24 upregulated and 36 downregulated genes in the hAβKI model, and 10 upregulated and 8 downregulated genes in the 5xFAD model. Notably, genes like KIF5B and GRASP were significantly downregulated, indicating impairment in vesicle homeostasis. The most significantly up- or downregulated genes differed across the three models (Figure 2). CONCLUSION: Our results show that the glutamatergic astrocyte signature varies in AD mouse models, with significant differences in their enrichment and gene expression profiles. The APP/PS1 and hAβKI models showed substantial enrichment of this astrocyte subtype, whereas the 5xFAD model exhibited minimal representation. The significant downregulation of genes related to vesicle trafficking suggests potential impairments in glutamatergic astrocyte function. Our findings highlight the role of a specific astrocyte subtype in AD pathogenesis. Further single-cell analysis will provide more information at the cellular level.
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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) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 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 | 0.000 |
| 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".