Female‐Specific Molecular Dysregulation in Alzheimer's Disease: miRNA and Gene Dynamics in 3xTg‐AD Mice
Bibliographic record
Abstract
BACKGROUND: Women are disproportionately affected by Alzheimer's disease (AD), accounting for approximately two-thirds of cases. This disparity arises from multifactorial factors, including greater longevity, hormonal changes, genetic and biological differences, cognitive reserve, lifestyle, and sex-specific pathophysiology. This study aims to investigate sex-specific differences in microRNAs (miRNAs)-key post-transcriptional and translational regulators of gene expression-and their associated roles in AD pathogenesis. METHOD: Using 3xTg-AD mice, which exhibit cognitive impairments at 3-4 months of age and carry three familial AD-associated mutations, along with their sibling controls, we analyzed animals of both sexes at 3, 6, and 12 months of age (4-6 animals per group). Fourteen miRNAs implicated in amyloidogenic, tauopathic, and inflammatory processes were screened in the neocortex-hippocampus using TaqMan Advanced single-tube miRNA assays. Additionally, 32 genes associated with amyloidogenic, tauopathic, and inflammatory pathways were analyzed in pooled neocortex-hippocampus via RT-qPCR for each age group, sex, and model. Relative expression levels were calculated as fold changes (>1.5-fold) using the comparative Ct method, with statistical significance (p < 0.05) determined by three-way ANOVA followed by Tukey's multiple comparison test. RESULT: Our analysis revealed significant miRNA dysregulation in female 3xTg-AD mice at 3 months of age (equivalent to humans in their 20s). Notably, amyloidogenic miRNAs (-15a, -29c, -101a, and -106b) were significantly downregulated in the neocortex-hippocampus. Among the 32 genes tested, 27 showed differential expression, with 17 genes exhibiting significant downregulation. However, transgene APP expression was significantly and consistently upregulated across all time points (3, 6, and 12 months), while transgene MAPT expression was significantly upregulated specifically at 3 months in females. Inflammatory cytokines (Il6, Tnf, and Lif) were significantly upregulated, whereas neuroinflammatory markers (Gfap, Aif1, and Trem2) were markedly downregulated in the neocortex-hippocampus. Additionally, genes related to APP clearance and microglial phenotypes, including Aqp4, Apoe, Abca1, Cfh, Clu, Cd68, Cx3cr1, P2ry12, Nfkb1, Stat3, and Sirt1, were also significantly downregulated. CONCLUSION: This study highlighted the vulnerability of female 3xTg-AD mice at 3 months of age, marked by amyloidogenic miRNA dysregulation and differential gene expression in the neocortex-hippocampus. However, sex-specific differences in miRNA and gene expression diminished with aging.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".