Lipocalin 2 Facilitates the Initial Compromise of the Blood–Brain Barrier Integrity in Chronic Cerebral Hypoperfusion
Bibliographic record
Abstract
AIMS: Vascular cognitive impairment (VCI) is primarily attributed to vascular risk factors and cerebrovascular disease. Chronic cerebral hypoperfusion (CCH) initiates in the early stages of VCI and contributes to blood-brain barrier (BBB) disruption. Nevertheless, the precise molecular mechanisms underlying this process remain elusive and warrant further investigation. METHODS: The Bilateral Carotid Artery Stenosis (BCAS) model was employed to simulate CCH, and the permeability of the BBB in the mouse frontal cortex was assessed at various time points post-operation. Transcriptome sequencing was conducted to identify differentially expressed genes (DEGs), which were then intersected with cortical gene chip data from human vascular dementia cases. Key genes identified through this analysis were subsequently measured in the serum of VCI patients and correlated with cognitive performance scores. Additionally, in vivo experiments were conducted to validate the influence of these key genes on BBB endothelial-mesenchymal transition (EndMT) and peripheral neutrophil infiltration. RESULTS: Time-course studies investigating BBB disruption revealed an increase in BBB permeability in the frontal cortex of mice on day 14 following BCAS, a stage at which the mice had not yet exhibited cognitive impairment. Subsequent sequencing analyses, integrated with human cortical gene expression profiles, identified Lipocalin 2 (LCN2) as a pivotal gene involved in mediating inflammatory responses and cell migration. Clinical studies have demonstrated that LCN2 is upregulated in the serum of patients with VCI and exhibits a significant negative correlation with Montreal Cognitive Assessment (MOCA) scores. Downregulation of LCN2 leads to a reduction in EndMT markers and peripheral neutrophil infiltration, as well as significant enhancements in learning and memory in BCAS mice through modulation of the MEK/ERK signaling pathway. CONCLUSION: This study elucidates the temporal characteristics and key molecular mechanisms underlying BBB disruption in the frontal cortex during CCH, thereby identifying novel potential targets for the early diagnosis and treatment of VCI.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".