Translational profiling identifies sex‐specific metabolic and epigenetic reprogramming of microglia in cerebral amyloidosis models with an antibiotic‐altered gut microbiome
Bibliographic record
Abstract
Abstract Background Microglia, the brain‐resident macrophages perform immune surveillance and engage in pathological processes by changing their phenotype and maintain homeostasis. Previously, we showed that antibiotic‐mediated changes in the gut microbiome of APPPS1‐21 transgenic mice resulted in significant decrease in amyloidosis and altered microglial phenotype that are specific to male mice. The molecular events underlying microglial phenotypic transition remain unclear due to lack of models that allow reliable in vivo proteomics. Here, we generated ‘APPPS1‐21‐CD11br’ microglia reporter mice and assessed their protein networks during their phenotypic transition in a sex‐specific manner. Method Six groups of mice that included WT‐CD11br, antibiotic (ABX) or vehicle‐treated APPPS1‐21‐CD11br male and female were sacrificed at 7‐weeks of age (n=15/group) and used for immunoprecipitation of microglial polysomes from cortical homogenates using anti‐FLAG antibody. Liquid chromatography coupled to tandem mass spectrometry (LC‐MSMS) and label‐free quantification was used to identify newly synthesized peptides extracted from polysomes Result We showed ABX‐treatment led to reduced Ab levels in male APPPS1‐21‐CD11br mice with no significant changes in the females. We first identified sex‐specific oxidative stress induced by Ab peptides leading to mitochondrial dysfunction and altered calcium signaling. Notably, the female mice also showed dysregulation of ribosomal machinery. Further, microglial polypeptides were associated with FcgR‐mediated phagocytosis in male mice and actin organization in female mice. Interestingly, ABX‐treatment resulted in substantial remodeling of epigenetic landscape for metabolic shift to accommodate increased bioenergetic and biosynthetic demands associated with microglial polarization in a sex‐specific manner. The male mice showed glycolytic shift for neuroprotective phenotype to promote Aβ clearance. However, the female mice showed loss of energy homeostasis due to persistent mitochondrial dysfunction associated with impaired lysosomal clearance and inflammatory phenotype. Conclusion Our studies provide first snapshot of the dynamic translational state of microglial cells in a sex‐specific manner. We identified that antibiotic‐mediated changes in gut microbiome results in metabolic reprogramming of microglial phenotypes to modulate immune responses and amyloid clearance. This microglial plasticity to support neuro‐energetic homeostasis for its function based on sex, paves the path for therapeutic modulation of immunometabolism for neurodegeneration.
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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 | 0.001 | 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 | 0.000 |
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".