Proteomic Quantification of Human Blood–Brain Barrier SLC and ABC Transporters in Healthy Individuals and Dementia Patients

The
blood–brain barrier (BBB) maintains brain homeostasis
by controlling traffic of molecules from the circulation into the
brain. This function is predominantly dependent on proteins expressed
at the BBB, especially transporters and tight junction proteins. Alterations
to the level and function of BBB proteins can impact the susceptibility
of the central nervous system to exposure to xenobiotics in the systemic
circulation with potential consequent effects on brain function. In
this study, expression profiles of drug transporters and solute carriers
in the BBB were assessed in tissues from healthy individuals (n = 12), Alzheimer’s patients (n = 5), and dementia with Lewy bodies patients (n = 5), using targeted, accurate mass retention time (AMRT) and global
proteomic methods. A total of 53 transporters were quantified, 19
for the first time in the BBB. A further 20 novel transporters were
identified but not quantified. The global proteomic method identified
another 3333 BBB proteins. Transporter abundances, taken together
with the scaling factor, microvessel protein content per unit tissue
(BMvPGB also measured here), can be used in quantitative systems pharmacology
models predicting drug disposition in the brain and permitting dose
adjustment (precision dosing) in special populations of patients,
such as those with dementia. Even in this small study, we see differences
in transporter profile between healthy and diseased brain tissue.

血脑屏障（blood–brain barrier，BBB）通过调控分子从循环系统进入大脑的转运过程，维持脑内稳态。这一功能主要依赖于血脑屏障上表达的蛋白质，尤其是转运蛋白与紧密连接蛋白。血脑屏障蛋白质的水平与功能异常，会影响中枢神经系统对体循环中外源化学物的暴露易感性，进而可能对脑功能造成潜在影响。本研究采用靶向精准质量保留时间（accurate mass retention time，AMRT）及全局蛋白质组学方法，对健康个体（n=12）、阿尔茨海默病患者（n=5）以及路易体痴呆患者（n=5）的血脑屏障组织中的药物转运蛋白与溶质载体的表达谱进行了分析。本研究共定量了53种转运蛋白，其中19种为首次在血脑屏障中被定量。另有20种新型转运蛋白被鉴定，但未进行定量分析。全局蛋白质组学方法另外鉴定出3333种血脑屏障相关蛋白质。转运蛋白丰度结合缩放因子——即每单位组织的微血管蛋白质含量（本研究同时测定了BMvPGB），可应用于定量系统药理学模型，用于预测药物在脑内的处置过程，并支持痴呆等特殊患者群体的剂量调整（精准给药）。即便本研究样本量较小，仍观察到健康脑组织与病变脑组织的转运蛋白表达谱存在差异。