Brain Endothelial Cells Produce Amyloid β from Amyloid Precursor Protein 770 and Preferentially Secrete the O-Glycosylated Form
Brain Endothelial Cells Produce Amyloid β from Amyloid Precursor Protein 770 and Preferentially Secrete the O-Glycosylated Form
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DOI：
10.1074/jbc.m110.144626
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发表时间：
2010-12-17
影响因子：
4.8
通讯作者：
Taniguchi, Naoyuki
中科院分区：
文献类型：
--
作者：
Kitazume, Shinobu;Tachida, Yuriko;Taniguchi, Naoyuki
大脑中淀粉样β蛋白(Aβ)的沉积与阿尔茨海默病(AD)密切相关。β是由淀粉样前体蛋白(APP)通过β-和伽马-分泌酶的作用产生的。除了脑实质中Aβ的沉积外，超过80%的AD患者还观察到Aβ在脑血管壁中的沉积，称为脑淀粉样血管病。Aβ如何在血管中积聚的机制在很大程度上仍不清楚。在目前的研究中，我们发现脑内皮细胞表达APP770，这是一种与神经元APP695不同的APP mRNA剪接亚型，并产生Aβ40和Aβ42。此外，我们还发现内皮APP770含有唾液酸化的核心型O-糖链。有趣的是，O-糖基化的APP770优先被α-和β-裂解处理并分泌到介质中，这表明O-糖基化和APP处理涉及相关的途径。用抗APP770抗体对人脑切片进行免疫染色，发现APP770在血管内皮细胞中表达。由于我们能够在人脑脊液中检测到O-糖基化的sAPP770β，这种独特的可溶性APP770β有可能作为皮质痴呆(如AD和血管性痴呆)的标志物。
Deposition of amyloid beta(A beta) in the brain is closely associated with Alzheimer disease (AD). A beta is generated from amyloid precursor protein (APP) by the actions of beta- and gamma-secretases. In addition to A beta deposition in the brain parenchyma, deposition of A beta in cerebral vessel walls, termed cerebral amyloid angiopathy, is observed in more than 80% of AD individuals. The mechanism for how A beta accumulates in blood vessels remains largely unknown. In the present study, we show that brain endothelial cells expressed APP770, a differently spliced APP mRNA isoform from neuronal APP695, and produced A beta 40 and A beta 42. Furthermore, we found that the endothelial APP770 had sialylated core 1 type O-glycans. Interestingly, O-glycosylated APP770 was preferentially processed by both alpha- and beta-cleavage and secreted into the media, suggesting that O-glycosylation and APP processing involved related pathways. By immunostaining human brain sections with an anti-APP770 antibody, we found that APP770 was expressed in vascular endothelial cells. Because we were able to detect O-glycosylated sAPP770 beta in human cerebrospinal fluid, this unique soluble APP770 beta has the potential to serve as a marker for cortical dementias such as AD and vascular dementia.