Sex‐specific changes in amyloidosis and neuro‐immune modulation in response to alterations in the gut microbiome
Bibliographic record
Abstract
Abstract Background Microglia, resident macrophages of CNS constantly screen the brain and engage in pathological processes by changing their morphology, expressing various antigens and become phagocytic. This activation causes the release of a wave of chemical mediators that promote the neuroinflammatory milieu. Thus, microglial homeostasis represents a highly plastic multifaceted response, finely tuned by the nature of the stimulus and the molecular repertoire involved. Studies from Sisodia lab have shown that antibiotic (ABX) mediated alterations of the gut microbiome in Thy1‐APPSwe.PS1L166Pmice (APPPS1‐21), resulted in a significant decrease in amyloidosis and altered microglial phenotypes in male mice. To investigate the influence of gut microbiome in modulating microglial function in a sex‐specific manner, we generated transgenic mice that would allow us to assess microglial RNA‐Protein networks and address the molecular mechanisms of CNS immunomodulation. Method We generated ‘Thy1‐APP.PS1‐RiboTag’ by crossing APPPS1‐21 mice to RiboTag mice wherein a CD11b promoter drives expression of ribosomal protein L10a (RpL10) that is fused to FLAG/EGFP at the amino‐terminus. Using our established protocol, we altered the microbiome of male and female mice (n=12) by orally gavaging them with ABX from day 14‐21, followed by low dose ABX in drinking water till they are sacrificed (7 wks). Vehicle treated mice were used as controls along with WT‐RiboTag mice. Immunoprecipitation of cortical homogenates with anti‐FLAG was performed to pull‐down actively translated mRNA and proteome in microglia following histopathology. Result We evaluated Aβ pathology and found that ABX‐treatment led to reduced amyloidosis in male mice with no significant changes in the female. Analysis of the mRNAs and the newly synthesized peptides resulted in a snapshot of the dynamic translational state of microglial ribosomes. We observed 21 upregulated and 22 downregulated proteins between the WT‐RiboTag and Th1‐APP.PS1‐RiboTag in male mice and 16 upregulated and 70 downregulated in female. Abx treatment resulted in upregulation of 39 and downregulation of 37 proteins in males while the females showed 51 and 9 respectively. Conclusion We find marked differences in the mRNA and proteins associated with microglial phenotypes expressed in a sex‐specific manner as a function of changes in the gut microbiome.
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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 | 0.000 |
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".