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

Abstract

Background In 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). Methods We 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. Results We 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. Conclusions These findings provide new insights on how vascular tPA can reach the brain parenchyma, and open therapeutic avenues for CNS disorders.

Parabiosis Discriminates the Circulating, Endothelial, and Parenchymal Contributions of Endogenous Tissue-Type Plasminogen Activator to Stroke

“…25,26 Conversely, under pathological conditions, the partnership between circulating tPA and endothelial NMDAR promotes bloodbrain barrier leakage and inflammation. 24,27 In addition to these direct effects on brain vasculature, tPA can also exit the bloodstream 28,29 and contribute to tPA within the brain parenchyma, leading to increased neuronal activity and potential neuronal loss. 17,30 Preclinical studies investigating the role and effect of tPA during ischemic stroke have yielded controversial findings, with some reporting beneficial outcomes [31][32][33] and others indicating deleterious effects.…”

“…25,26 Conversely, under pathological conditions, the partnership between circulating tPA and endothelial NMDAR promotes blood-brain barrier leakage and inflammation. 24,27 In addition to these direct effects on brain vasculature, tPA can also exit the bloodstream 28,29 and contribute to tPA within the brain parenchyma, leading to increased neuronal activity and potential neuronal loss. 17,30…”