Background:A strong body of evidence suggests that cerebrovascular pathologies augment the onset and progression of Alzheimer’s disease (AD). One distinctive aspect of this cerebrovascular dysfunction is the degeneration of brain pericytes—often overlooked supporting cells of blood-brain barrier endothelium. Objective:The current study investigates the influence of pericytes on gene and protein expressions in the blood-brain barrier endothelium, which is expected to facilitate the identification of pathophysiological pathways that are triggered by pericyte loss and lead to blood-brain barrier dysfunction in AD. Methods:Bioinformatics analysis was conducted on the RNA-Seq expression counts matrix (GSE144474), which compared solo-cultured human blood-brain barrier endothelial cells against endothelial cells co-cultured with human brain pericytes in a non-contact model. We constructed a similar cell culture model to verify protein expression using western blots. Results:The insulin resistance and ferroptosis pathways were found to be enriched. Western blots of the insulin receptor and heme oxygenase expressions were consistent with those observed in RNA-Seq data. Additionally, we observed more than 5-fold upregulation of several genes associated with neuroprotection, including insulin-like growth factor 2 and brain-derived neurotrophic factor. Conclusions:Results suggest that pericyte influence on blood-brain barrier endothelial gene expression confers protection from insulin resistance, iron accumulation, oxidative stress, and amyloid deposition. Since these are conditions associated with AD pathophysiology, they imply mechanisms by which pericyte degeneration could contribute to disease progression.

中文翻译：

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血脑屏障内皮基因表达的周细胞控制：对阿尔茨海默病的影响

背景：大量证据表明，脑血管病变会加剧阿尔茨海默病 (AD) 的发病和进展。这种脑血管功能障碍的一个独特方面是脑周细胞的退化——经常被忽视的血脑屏障内皮支持细胞。目的：本研究探讨周细胞对血脑屏障内皮基因和蛋白表达的影响，以期有助于识别AD中周细胞丢失引发并导致血脑屏障功能障碍的病理生理通路。方法：对RNA-Seq表达计数矩阵（GSE144474）进行生物信息学分析，在非接触模型中比较单独培养的人血脑屏障内皮细胞与与人脑周细胞共培养的内皮细胞。我们构建了类似的细胞培养模型，以使用蛋白质印迹验证蛋白质表达。结果：发现胰岛素抵抗和铁死亡途径丰富。胰岛素受体和血红素加氧酶表达的蛋白质印迹与 RNA-Seq 数据中观察到的结果一致。此外，我们观察到一些与神经保护相关的基因上调了 5 倍以上，包括胰岛素样生长因子 2 和脑源性神经营养因子。结论：结果表明，周细胞对血脑屏障内皮基因表达的影响可防止胰岛素抵抗、铁积累、氧化应激和淀粉样蛋白沉积。由于这些是与 AD 病理生理学相关的病症，因此它们暗示了周细胞变性可能导致疾病进展的机制。