IsoDGR-Induced Endothelial Cytoskeletal Disruption Drives Age-Related Blood-Brain Barrier Breakdown
Bibliographic record
Abstract
ABSTRACT Brain aging is characterized by progressive breakdown of the blood-brain barrier (BBB), which correlates with neuroinflammation and cognitive decline. Emerging evidence implicates degenerative modifications of the vascular proteins as a key driver of BBB dysfunction. In particular, spontaneous deamidation of Asp-Gly-Arg (NGR) motifs generates isoAsp-Gly-Arg (isoDGR) sequences that structurally mimic canonical Arg-Gly-Asp (RGD) integrin-binding ligands. Here, we show that age-associated accumulation of isoDGR in the brain cortex induces endothelial cytoskeletal collapse and tight junction disorganization, leading to BBB breakdown. Using mice lacking the L-isoaspartyl repair enzyme PCMT1 (which accelerates isoDGR accumulation) and wild type aged mice, we found markedly elevated isoDGR in brain tissues accompanied by focal microhemorrhages and increased BBB permeability. Recent whole-genome sequencing suggests that a common PCMT1 variant is linked to neurodegenerative disease risk, indicating potential clinical relevance in vascular aging. Remarkably, systemic treatment with an isoDGR-neutralizing antibody largely prevented capillary breaches and leakage, and even restored barrier integrity in aged wild-type mice. To uncover the molecular mechanism, we exposed brain endothelial cells to synthetic isoDGR-peptides, which recapitulated these effects. Unbiased RNA-sequencing reinforced these findings, revealing broad transcriptomic reprogramming of cytoskeletal, cell-cell junction, inflammatory, and stress-response pathways. Functional studies demonstrated that isoDGR triggered collapse of F-actin stress fibers, disrupted junctional ZO-1 and VE-cadherin, increased monolayer permeability to macromolecules, and impaired endothelial cell migration and proliferation. IsoDGR-treated endothelial cells exhibited increased oxidative stress, upregulation of ICAM-1/VCAM-1/CCL-2, and adopted a senescent phenotype. Our results suggest that isoDGR hijacks endothelial integrin signaling to destabilize the actin cytoskeleton and tight junctions, a process that breaches the BBB and subsequently activates inflammatory and senescence programs. In summary, we identify BBB disruption via isoDGR-induced cytoskeletal dysfunction as a central pathology of vascular aging, and demonstrate that targeting isoDGR damage preserves BBB integrity and attenuates neuroinflammation.
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) | 0.000 | 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) | 0.001 | 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".