Nie Qianqian, Zhang Liren, Gu Zhengsheng, Li Yuchao, Bi Xiaoying
Department of Neurology, Changhai Hospital, Naval Medical University, Shanghai, China.
Department of Nuclear Medicine, Changhai Hospital, Naval Medical University, Shanghai, China.
CNS Neurosci Ther. 2025 May;31(5):e70438. doi: 10.1111/cns.70438.
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.
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.
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.
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.
血管性认知障碍（VCI）主要归因于血管危险因素和脑血管疾病。慢性脑灌注不足（CCH）在VCI的早期阶段就已开始，并导致血脑屏障（BBB）破坏。然而，这一过程背后的确切分子机制仍不清楚，值得进一步研究。
采用双侧颈动脉狭窄（BCAS）模型模拟CCH，并在术后不同时间点评估小鼠额叶皮质中BBB的通透性。进行转录组测序以鉴定差异表达基因（DEG），然后将这些基因与来自人类血管性痴呆病例的皮质基因芯片数据进行比对。通过该分析确定的关键基因随后在VCI患者的血清中进行检测，并与认知表现评分相关联。此外，进行体内实验以验证这些关键基因对BBB内皮-间充质转化（EndMT）和外周中性粒细胞浸润的影响。
对BBB破坏的时间进程研究显示，BCAS术后第14天小鼠额叶皮质中的BBB通透性增加，此时小鼠尚未表现出认知障碍。随后的测序分析与人类皮质基因表达谱相结合，确定脂质运载蛋白2（LCN2）是参与介导炎症反应和细胞迁移的关键基因。临床研究表明，VCI患者血清中LCN2上调，并且与蒙特利尔认知评估（MOCA）评分呈显著负相关。LCN2的下调导致EndMT标志物和外周中性粒细胞浸润减少，并且通过调节MEK/ERK信号通路显著增强了BCAS小鼠的学习和记忆能力。
本研究阐明了CCH期间额叶皮质中BBB破坏的时间特征和关键分子机制，从而为VCI的早期诊断和治疗确定了新的潜在靶点。
