Amyloid β Oligomers Disrupt Blood-CSF Barrier Integrity by Activating Matrix Metalloproteinases
Amyloid β Oligomers Disrupt Blood-CSF Barrier Integrity by Activating Matrix Metalloproteinases
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DOI：
10.1523/jneurosci.0006-15.2015
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发表时间：
2015-09-16
影响因子：
5.3
通讯作者：
Vandenbroucke, Roosmarijn E.
中科院分区：
文献类型：
--
作者：
Brkic, Marjana;Balusu, Sriram;Vandenbroucke, Roosmarijn E.
血-CSF屏障（BCSFB）由单层脉络丛上皮（CPE）细胞组成，通过产生CSF和限制不需要的分子和病原体进入大脑来维持CNS稳态。阿尔茨海默病是最常见的进行性神经退行性疾病，其特征在于脑中存在淀粉样蛋白β（A β）斑块和神经元缠结。最近的研究表明，阿尔茨海默病与CPE细胞的形态学变化和CSF的产生受损有关。在这里，我们研究了A β对BCSFB功能的直接影响。将A β 1-42寡聚体脑室内注射到小鼠脑室（一种经验证的阿尔茨海默病模型）中，引起了一系列有害事件的诱导，包括CPE细胞中炎性基因表达增加和CSF中促炎细胞因子和趋化因子水平增加。它还迅速影响CPE细胞形态和紧密连接蛋白水平。这些变化与BCSFB完整性的丧失有关，如BCSFB泄漏增加所示。A β 1-42寡聚体也增加CPE中的基质金属蛋白酶（MMP）基因表达及其在CSF中的活性。有趣的是，A β 1-42寡聚体诱导的BCSFB破坏在广谱MMP抑制剂存在下或MMP 3缺陷小鼠中不发生。这些数据提供了证据，证明MMP对于A β 1-42寡聚体诱导的BCSFB渗漏是必需的。我们的研究结果表明，阿尔茨海默病相关的可溶性A β 1-42寡聚体诱导BCSFB功能障碍，并建议MMPs作为一个可能的治疗靶点。
The blood-CSF barrier (BCSFB) consists of a monolayer of choroid plexus epithelial (CPE) cells that maintain CNS homeostasis by producing CSF and restricting the passage of undesirable molecules and pathogens into the brain. Alzheimer's disease is the most common progressive neurodegenerative disorder and is characterized by the presence of amyloid beta (A beta) plaques and neurofibrillary tangles in the brain. Recent research shows that Alzheimer's disease is associated with morphological changes in CPE cells and compromised production of CSF. Here, we studied the direct effects of A beta on the functionality of the BCSFB. Intracerebroventricular injection of A beta 1-42 oligomers into the cerebral ventricles of mice, a validated Alzheimer's disease model, caused induction of a cascade of detrimental events, including increased inflammatory gene expression in CPE cells and increased levels of proinflammatory cytokines and chemokines in the CSF. It also rapidly affected CPE cell morphology and tight junction protein levels. These changes were associated with loss of BCSFB integrity, as shown by an increase in BCSFB leakage. A beta 1-42 oligomers also increased matrix metalloproteinase (MMP) gene expression in the CPE and its activity in CSF. Interestingly, BCSFB disruption induced by A beta 1-42 oligomers did not occur in the presence of a broad-spectrum MMP inhibitor or in MMP3-deficient mice. These data provide evidence that MMPs are essential for the BCSFB leakage induced by A beta 1-42 oligomers. Our results reveal that Alzheimer's disease-associated soluble A beta 1-42 oligomers induce BCSFB dysfunction and suggest MMPs as a possible therapeutic target.