小柯机器人

血脑屏障会随年龄变化而受损
2020-07-03 14:04

近日,美国斯坦福大学医学院Tony Wyss-Coray小组的最新工作表明,生理性血脑运输会随着年龄的增长受到损害。2020年7月1日,《自然》在线发表了这一成果。

研究人员标记了构成小鼠血浆蛋白质组的数百种蛋白质,并且在其全身性给药后,研究了血脑屏障(BBB)及其生理配体。研究人员发现血浆蛋白很容易渗入健康的脑实质,并由BBB特异性转录程序维持转运。与IgG抗体不同,血浆中蛋白质的摄取在衰老的大脑中减少,这是由与年龄相关的从配体特异性受体介导的转运到非特异性转胞吞作用。
 
这种与年龄有关的转变与周细胞覆盖率的特定损失同时发生。随年龄上调的磷酸酶ALPL(一种预测的转运负调节因子)的药理抑制作用可增强大脑对治疗相关的转铁蛋白、转铁蛋白受体抗体和血浆的摄取。
 
这些发现揭示了生理蛋白转入健康大脑的程度,一种随着年龄增长而广泛产生血脑屏障功能障碍的机制,以及一种增强药物传递的策略。
 
据了解,大脑的血管界面被称为BBB,其参与维持大脑功能,部分是通过其较低的跨细胞渗透性。然而,最近的研究表明,大脑衰老对循环蛋白敏感。因此,目前尚不清楚个别注射的外源示踪剂的渗透性是否完全代表了血脑转移能力。
 
附:英文原文

Title: Physiological blood–brain transport is impaired with age by a shift in transcytosis

Author: Andrew C. Yang, Marc Y. Stevens, Michelle B. Chen, Davis P. Lee, Daniel Sthli, David Gate, Kvin Contrepois, Winnie Chen, Tal Iram, Lichao Zhang, Ryan T. Vest, Aisling Chaney, Benoit Lehallier, Niclas Olsson, Haley du Bois, Ryan Hsieh, Haley C. Cropper, Daniela Berdnik, Lulin Li, Elizabeth Y. Wang, Gavin M. Traber, Carolyn R. Bertozzi, Jian Luo, Michael P. Snyder, Joshua E. Elias, Stephen R. Quake, Michelle L. James, Tony Wyss-Coray

Issue&Volume: 2020-07-01

Abstract: The vascular interface of the brain, known as the blood–brain barrier (BBB), is understood to maintain brain function in part via its low transcellular permeability1,2,3. Yet, recent studies have demonstrated that brain ageing is sensitive to circulatory proteins4,5. Thus, it is unclear whether permeability to individually injected exogenous tracers—as is standard in BBB studies—fully represents blood-to-brain transport. Here we label hundreds of proteins constituting the mouse blood plasma proteome, and upon their systemic administration, study the BBB with its physiological ligand. We find that plasma proteins readily permeate the healthy brain parenchyma, with transport maintained by BBB-specific transcriptional programmes. Unlike IgG antibody, plasma protein uptake diminishes in the aged brain, driven by an age-related shift in transport from ligand-specific receptor-mediated to non-specific caveolar transcytosis. This age-related shift occurs alongside a specific loss of pericyte coverage. Pharmacological inhibition of the age-upregulated phosphatase ALPL, a predicted negative regulator of transport, enhances brain uptake of therapeutically relevant transferrin, transferrin receptor antibody and plasma. These findings reveal the extent of physiological protein transcytosis to the healthy brain, a mechanism of widespread BBB dysfunction with age and a strategy for enhanced drug delivery.

DOI: 10.1038/s41586-020-2453-z

Source: https://www.nature.com/articles/s41586-020-2453-z

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

分享到:

0