mTOR signaling regulates microglia metabolism and survival via 4E‐BP‐controlled mRNA translation
Bibliographic record
Abstract
Abstract Background Rare loss‐of‐function variants in TREM2 (Triggering Receptor Expressed in Myeloid cells 2) are associated with an increased risk of AD. There are ongoing efforts to therapeutically boost microglial neuroprotective functions by targeting TREM2. However, the intracellular mechanisms underlying these functions in AD are not fully understood. TREM2 signaling maintains metabolic fitness through activation of the mechanistic target of rapamycin (mTOR) allowing microglia to sustain their metabolism during amyloidosis (Ulland et al., 2017). Detrimental decreases in microglial mTOR signalling during amyloidosis independent of TREM2 loss‐of‐function has also been reported (Baik et al., 2019). The mTOR pathway acts upstream of the eukaryotic mRNA translation by suppressing the translation repressor, eukaryotic translation initiation factor 4E (eIF4E)‐binding proteins (4E‐BPs). mTOR inhibits the 4E‐BPs via phosphorylation, thereby releasing eIF4E and allowing mRNA translation to initiate (Hay and Sonenberg, 2004). Work from our group demonstrated that mTOR boosts mitochondrial metabolism through 4E‐BP‐controlled mRNA translation (Morita et al., 2013). Therefore, we aimed to understand the dysregulated mechanisms at the intersection of mTOR‐controlled mRNA translation and metabolism in microglia response to Amyloid‐β (Aß). Method We used immunoblotting to investigate the effect on 4E‐BP phosphorylation following chronic exposure to Aß aggregates and TREM2 signaling inhibition in a microglia cell line. We manipulated the mTOR pathway by knocking out the downstream effectors, 4E‐BPs, to promote the translation of 4E‐BP‐controlled mRNAs in microglia in vitro and in vivo. We crossed the microglia‐specific 4E‐BPs knock out mouse with a RiboTag mouse to pull‐down ribosome‐bound mRNAs, providing a genome‐wide pool of actively translating mRNAs (the translatome) in the absence of 4E‐BPs in microglia. Result We showed that 4E‐BP‐controlled mRNA translation is inhibited upon chronic exposure to Aß or TREM2 signaling inhibition. The deletion of 4E‐BPs in microglia in‐vitro leads to a decrease in expression of pro‐inflammatory mediators and microglia cell death, and an increase in reliance on oxidative phosphorylation upon exposure to Aß. We also observed that 4E‐BP deletion changes the microglia translatome and decreases expression of inflammatory mediators in vivo after an intracranial Aß infusion. Conclusion We conclude that mTOR signaling exerts key effects on microglia function and metabolism through 4E‐BP‐controlled mRNA translation.
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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 | 0.000 |
| 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 | 0.001 |
| 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".