The choroid plexus: a door between the blood and the brain for tissue-type plasminogen activator

Fluids and Barriers of the CNS

Research

Sara Martinez de Lizarrondo¹  Yannick Hommet¹  Laurent Lebouvier¹  Marina Rubio¹  Jonathane Furon¹  Mathys Bellemain-Sagnard¹  Carine Ali¹  Vincent Zuba¹  Maxime Gauberti¹  Denis Vivien² 

[1]Physiopathology and Imaging of Neurological Disorders, Normandie Univ, UNICAEN, INSERM, INSERM UMR-S U1237, Institut Blood and Brain @ Caen-Normandie, GIP Cyceron, Boulevard Becquerel, 14074, Caen, France

[2]Physiopathology and Imaging of Neurological Disorders, Normandie Univ, UNICAEN, INSERM, INSERM UMR-S U1237, Institut Blood and Brain @ Caen-Normandie, GIP Cyceron, Boulevard Becquerel, 14074, Caen, France

[3]Department of Clinical Research, Caen-Normandie Hospital (CHU), Caen, France

关键词: Tissue-type plasminogen activator;    Choroid plexus;    Epithelium;    Low density lipoprotein receptor-related protein;    Barrier;    Transport;    Finger domain;    Drug delivery;   

DOI  :  10.1186/s12987-022-00378-0

 received in 2022-03-23, accepted in 2022-10-10,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundIn the vascular compartment, the serine protease tissue-type plasminogen activator (tPA) promotes fibrinolysis, justifying its clinical use against vasculo-occlusive diseases. Accumulating evidence shows that circulating tPA (endogenous or exogenous) also controls brain physiopathological processes, like cerebrovascular reactivity, blood–brain barrier (BBB) homeostasis, inflammation and neuronal fate. Whether this occurs by direct actions on parenchymal cells and/or indirectly via barriers between the blood and the central nervous system (CNS) remains unclear. Here, we postulated that vascular tPA can reach the brain parenchyma via the blood-cerebrospinal fluid barrier (BCSFB), that relies on choroid plexus (CP) epithelial cells (CPECs).MethodsWe produced various reporter fusion proteins to track tPA in primary cultures of CPECs, in CP explants and in vivo in mice. We also investigated the mechanisms underlying tPA transport across the BCSFB, with pharmacological and molecular approaches.ResultsWe first demonstrated that tPA can be internalized by CPECs in primary cultures and in ex vivo CPs explants. In vivo, tPA can also be internalized by CPECs both at their basal and apical sides. After intra-vascular administration, tPA can reach the cerebral spinal fluid (CSF) and the brain parenchyma. Further investigation allowed discovering that the transcytosis of tPA is mediated by Low-density-Lipoprotein Related Protein-1 (LRP1) expressed at the surface of CPECs and depends on the finger domain of tPA. Interestingly, albumin, which has a size comparable to that of tPA, does not normally cross the CPs, but switches to a transportable form when grafted to the finger domain of tPA.ConclusionsThese findings provide new insights on how vascular tPA can reach the brain parenchyma, and open therapeutic avenues for CNS disorders.

【 授权许可】

CC BY   
© The Author(s) 2022. Corrected publication 2022

【 图 表 】

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