Beta-Secretase 1 Underlies Reactive Astrocytes and Endothelial Disruption in Neurodegeneration.
Beta-Secretase 1 Underlies Reactive Astrocytes and Endothelial Disruption in Neurodegeneration.
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DOI：
10.3389/fncel.2021.656832
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发表时间：
2021
影响因子：
5.3
通讯作者：
Cardona-Gómez GP
中科院分区：
文献类型：
--
作者：
Chacón-Quintero MV;Pineda-López LG;Villegas-Lanau CA;Posada-Duque R;Cardona-Gómez GP
神经血管单位（NVU）功能障碍是阿尔茨海默病（AD）进行性恶化的关键组成部分，在血管性痴呆中至关重要。最近的研究表明，炎症在与NVU损伤相关的AD发病机制中起早期和可能的因果作用，可能部分通过过度激活β位点淀粉样前体蛋白裂解酶1（BACE 1）的天冬氨酸蛋白酶活性，迄今为止几乎仅在β-淀粉样蛋白级联的背景下进行了研究。在这项研究中，我们分析了BACE 1与散发性和家族性痴呆[常染色体显性遗传性脑动脉病伴皮质下梗死和白质脑病（CADASIL），散发性阿尔茨海默病（SAD）和家族性阿尔茨海默病（FAD）]人脑星形胶质细胞和血管的关系，以及BACE 1抑制如何在谷氨酸毒性条件下影响星形胶质细胞和内皮细胞。我们的研究结果表明，增加BACE 1，PHF（配对螺旋丝）-tau和GFAP（胶质纤维酸性蛋白）免疫反应性（IR）在CA 1海马区的FAD和SAD的大脑。此外，在所有研究病例的组织样本中，BACE 1与GFAP免疫沉淀，但它们的免疫荧光接近（10 μm3）或重叠的血管仅在FAD和SAD脑中增加，并且PHF-tau主要存在于FAD脑中的血管周围。有趣的是，增加的BACE 1水平与反应性星形胶质细胞相关，其特征在于病理和应激条件下的形态学变化和GFAP上调，以及谷氨酸兴奋性毒性引起的内皮破坏，并且这些作用被BACE 1抑制逆转;此外，BACE 1抑制的星形胶质细胞通过保护闭合小带-1（ZO-1）保护内皮细胞完整性分布和减少炎症标志物的表达。总之，这些发现表明星形胶质细胞中的BACE 1失调可能在涉及神经变性的NVU完整性的改变中起作用。
Dysfunction in the neurovascular unit (NVU) is a key component in the progressive deterioration of Alzheimer’s disease (AD) and is critical in vascular dementia. Recent studies have shown that inflammation plays early and perhaps causal roles in the pathogenesis of AD related to NVU damage, possibly in part by overactivating the aspartic acid protease activity of β-site amyloid precursor protein-cleaving enzyme 1 (BACE1), which until now has almost solely been studied in the context of the β-amyloid cascade. In this study, we analyzed the relationship of BACE1 with astrocytes and blood vessels in human brains with sporadic and familial dementia [Autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), sporadic Alzheimer’s disease (SAD), and familial Alzheimer’s disease (FAD)] and how BACE1 inhibition affects astrocytes and endothelial cells under conditions of glutamate toxicity. Our results show increased BACE1, PHF (Paired helical filaments)-tau and GFAP (Glial Fibrillary Acid Protein) immunoreactivity (IR) in the CA1 hippocampal regions of FAD and SAD brains. Furthermore, BACE1 immunoprecipitated with GFAP in tissue samples from all study cases, but their immunofluorescence close to (10 μm3) or overlapping blood vessels was only increased in FAD and SAD brains, and PHF-tau was present around the vessels mainly in FAD brains. Interestingly, the increased BACE1 levels were associated with reactive astrocytes, characterized by morphological changes and upregulation of GFAP under pathological and stressful conditions, and endothelial disruption by glutamate excitotoxicity, and these effects were reversed by BACE1 inhibition; further, BACE1-inhibited astrocytes protected endothelial cell integrity by preserving zonula occludens-1 (ZO-1) distribution and decreasing the expression of inflammatory markers. Taken together, these findings suggest that BACE1 dysregulation in astrocytes may have a role in the alterations in NVU integrity implicated in neurodegeneration.
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影响因子：
11.1
作者：
del Zoppo GJ
通讯作者：
del Zoppo GJ
影响因子：
5.3
作者：
Posada-Duque RA;Barreto GE;Cardona-Gomez GP
通讯作者：
Cardona-Gomez GP
影响因子：
4.1
作者：
Docagne, F;Gabriel, C;Vivien, D
通讯作者：
Vivien, D
影响因子：
12.7
作者：
Botez, G;Probst, A;Tolnay, M
通讯作者：
Tolnay, M
非神经元和神经元 BACE1 升高与人脑血管病和软脑膜 β-淀粉样蛋白沉积相关
影响因子：
2.6
作者：
Xue ZQ;He ZW;Yu JJ;Cai Y;Qiu WY;Pan A;Gai WP;Cai H;Luo XG;Ma C;Yan XX
通讯作者：
Yan XX