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 permeability 1 – 3 . Yet, recent studies have demonstrated that brain ageing is sensitive to circulatory proteins 4 , 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. Tagging and tracking the blood plasma proteome as a discovery tool reveals widespread endogenous transport of proteins into the healthy brain and the pharmacologically modifiable mechanisms by which the brain endothelium regulates this process with age.

中文翻译：

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生理性血脑转运因转胞吞作用的变化而随着年龄的增长而受损

大脑的血管界面，被称为血脑屏障 (BBB)，被认为部分通过其低跨细胞渗透性来维持大脑功能 1-3 。然而，最近的研究表明，大脑衰老对循环蛋白很敏感 4 、 5 。因此，尚不清楚单独注射的外源性示踪剂的渗透性（如 BBB 研究中的标准）是否完全代表血脑转运。在这里，我们标记了构成小鼠血浆蛋白质组的数百种蛋白质，并在全身给药后，研究 BBB 及其生理配体。我们发现血浆蛋白很容易渗透到健康的脑实质中，运输由 BBB 特异性转录程序维持。与 IgG 抗体不同，老年大脑中血浆蛋白的摄取减少，由与年龄相关的转运从配体特异性受体介导到非特异性小窝胞吞作用的转变驱动。这种与年龄相关的转变与周细胞覆盖率的特定损失同时发生。对年龄上调的磷酸酶 ALPL（一种预测的转运负调节剂）的药理学抑制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性蛋白质转胞吞作用对健康大脑的影响程度、随着年龄的增长而广泛存在的 BBB 功能障碍的机制以及增强药物输送的策略。标记和跟踪血浆蛋白质组作为一种发现工具，揭示了蛋白质向健康大脑的广泛内源性转运，以及大脑内皮随着年龄的增长调节这一过程的药理学可改变机制。