A common risk variant in the <i>MTHFR</i> gene contributes to age‐related cerebrovascular dysfunction in VCID
Bibliographic record
Abstract
Abstract Background Cerebrovascular damage occurs during aging, Alzheimer’s disease and Vascular Dementia, commonly referred to as Vascular Contributions to Cognitive Impairment and Dementia (VCID). However, few mouse models currently recapitulate human cerebrovascular deficiencies in disease. The C677T variant in methylenetetrahydrofolate reductase (MTHFRC677T ) is commonly associated with VCID. MTHFR codes for an enzyme involved in production of folate, homocysteine, and methionine metabolism. The MTHFRC677T polymorphism is predicted to result in hyperhomocysteinemia, a condition that causes vascular inflammation and vascular damage. Additionally, methionine deficiency can result in DNA hypomethylation and has been confirmed in MTHFRC677T carriers. Despite the fact that, in some populations, MTHFRC677T is more common than APOE E4, mechanisms by which MTHFR C677T increases risk for VCID are not known. Methods CRISPR technology was employed to engineer the Mthfr C677T allele into C57BL/6J (B6) mice. Vascular health is being assessed in 6, 12, 18 and 24 months‐old mice using leakage assays (FITC‐dextran and presence of extravascular fibrin) and immunofluorescence (IF) to examine blood brain barrier integrity in the cerebrovascular unit: endothelium (CD31) smooth muscle (aSMA) pericytes (PDGRFb) basement membrane (ColIV) and tight junctions (Claudin‐5, Occludin, ZO‐1). Functional MRI is used to determine in vivo vascular reactivity. Bulk RNA sequencing and Reduced Representation Bisulfite Sequencing (RRBS) were performed on half brains to assess differential gene expression and DNA methylation, respectively. Results Mice with the Mthfr C677T risk variant have significantly reduced liver enzymatic activity, significantly increased plasma homocysteine levels and decreased methionine levels, recapitulating the human phenotype. Transcriptional profiling of brain tissue revealed genes regulating circadian rhythm, neurogenesis, ER stress and GABA signaling are differentially expressed (DE) in B6.Mthfr C677T compared to B6 samples. RRBS data demonstrated significant genome‐wide DNA hypomethylation in these mice. Hypomethylated and DE genes are expressed in astrocytes, microglia and endothelial cells and are predicted to regulate apoptosis/proliferation, inflammation and glucose transport across the blood brain barrier. Validation by IF is underway. Conclusion We have created a novel mouse strain to determine the precise mechanisms by which MTHFR C677T increases risk for VCID. This work aims to identify novel therapeutic approaches that preserve cerebrovascular health throughout aging to prevent VCID.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 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) | 0.005 | 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".