A Tale of Two Mice: Altered TREM2 Signalling Contributes to the Disparate Alzheimer's Disease Pathological Phenotypes Observed in ABI3‐Deficient Transgenic CRND8 and 5XFAD mice
Bibliographic record
Abstract
BACKGROUND: Alzheimer's disease (AD) remains the leading cause of dementia worldwide and currently lacks effective therapies. Recent studies have identified AD-associated genetic variants in several microglial-enriched genes, highlighting microglia as key contributors to disease pathogenesis and as promising therapeutic targets. These include several risk variants in Trem2 and a rare coding risk variant in Abi3 (rs616338:p. Ser209Phe). The impact of ABI3 deletion on AD pathology remains inconclusive as recent studies in ABI3-deficient AD mouse models have produced conflicting observations. Specifically, the deletion of ABI3 reduces amyloid phenotypes in the TgCRND8 transgenic mouse model but exacerbates these phenotypes in the 5XFAD mouse model. We hypothesize that TREM2 signalling differences in C57 (genetic background of TgCRND8) and SJL (genetic background of 5XFAD) microglia contribute to this discrepancy. METHOD: Using primary mouse microglia derived from C57 and SJL mice, we analyzed TREM2 cleavage by ELISA and TREM2 signalling by stimulating the cells using an activating antibody and measuring SYK and PLCG2 phosphorylations (validated components of TREM2 signalling pathway) by western blotting. In addition, we compared TREM2-dependent phagocytosis of amyloid-beta by C57 and SJL microglia using IncuCyte S3 live imaging. RESULT: We observed significant alterations in TREM2 signalling in SJL microglia compared to C57 microglia. TREM2 cleavage was significantly lower in SJL microglia and following stimulation by an anti-TREM2 activating antibody, SJL microglia demonstrated attenuated SYK and PLCG2 phosphorylations and reduced amyloid-beta phagocytosis compared to C57 microglia. CONCLUSION: We have demonstrated that TREM2 signalling and the related AD-associated functions are significantly altered in SJL microglia. In addition, previous co-expression network analyses have suggested a close functional relationship between TREM2 and ABI3. A combined presence of altered TREM2 signalling and ABI3 deletion may explain the diverging phenotypes observed in TgCRND8 and 5XFAD mouse models. We are currently investigating other potential contributing factors such as differences in genetic background and AD transgenes expressed in these mouse models. We aim to uncover the molecular machinery that links TREM2 to ABI3 in microglia and to understand the impact of ABI3 S209F mutation on TREM2 signalling in microglia and in AD pathology, pathing the way towards identifying novel therapeutics.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.003 |
| Insufficient payload (model declined to judge) | 0.006 | 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".