Research Article: Trafficking of immune cells across the blood-brain barrier is modulated by neurofibrillary pathology in tauopathies

Date Published: May 23, 2019

Publisher: Public Library of Science

Author(s): Petra Majerova, Alena Michalicova, Martin Cente, Jozef Hanes, Jozef Vegh, Agnes Kittel, Nina Kosikova, Viera Cigankova, Sandra Mihaljevic, Santosh Jadhav, Andrej Kovac, Emmanuel Planel.

http://doi.org/10.1371/journal.pone.0217216

Abstract

Tauopathies represent a heterogeneous group of neurodegenerative disorders characterized by abnormal deposition of the hyperphosphorylated microtubule-associated protein tau. Chronic neuroinflammation in tauopathies is driven by glial cells that potentially trigger the disruption of the blood-brain barrier (BBB). Pro-inflammatory signaling molecules such as cytokines, chemokines and adhesion molecules produced by glial cells, neurons and endothelial cells, in general, cooperate to determine the integrity of BBB by influencing vascular permeability, enhancing migration of immune cells and altering transport systems. We considered the effect of tau about vascular permeability of peripheral blood cells in vitro and in vivo using primary rat BBB model and transgenic rat model expressing misfolded truncated protein tau. Immunohistochemistry, electron microscopy and transcriptomic analysis were employed to characterize the structural and functional changes in BBB manifested by neurofibrillary pathology in a transgenic model. Our results show that misfolded protein tau ultimately modifies the endothelial properties of BBB, facilitating blood-to-brain cell transmigration. Our results suggest that the increased diapedesis of peripheral cells across the BBB, in response to tau protein, could be mediated by the increased expression of endothelial signaling molecules, namely ICAM-1, VCAM-1, and selectins. We suggest that the compensation of BBB in the diseased brain represents a crucial factor in neurodegeneration of human tauopathies.

Partial Text

Neuroinflammation manifests before a significant loss of neural tissue in the process of neurodegeneration, suggesting that neuroinflammation promotes the progression of pathogenesis in neurodegenerative diseases. In neurodegenerative diseases associated with chronic neuroinflammation, immune responses driven by the main reactive components of the central nervous system (CNS) including glial cells leading to the disruption of the blood-brain barrier (BBB). Inflammatory processes affect the structure and function of BBB by increasing its vascular permeability, enhancing transmigration of peripheral blood-borne immune cells, modifying the transport systems by influencing the BBB as signaling interface [1]. Pro-inflammatory signaling molecules such as cytokines, chemokines and adhesion molecules produced by astrocytes, microglial cells, oligodendrocytes, neurons, and endothelial cells cooperate to influence the properties of BBB and regulate leukocyte-endothelial adhesion, moderate inflammation and can influence the disease pathology [2, 3]. Although the role of neuroinflammation during neurodegeneration remains unclear, findings stemming from experimental models and clinical studies have demonstrated a significant contribution of inflammation to pathological features and symptoms.

In recent years, studies investigating the dysfunction and malfunction of brain barriers in the pathogenesis of tauopathies have gained prominence. In this study, we analyzed the mechanisms by which misfolded protein tau induce structural and functional changes of BBB, and facilitate the transmigration of blood-borne cells into the brain. Using transgenic rat model of tauopathy (line SHR-72) with progressive age-dependent neurofibrillary degeneration in the brainstem [28, 32], and well established in vitro BBB model [31], we demonstrate that misfolded tau deregulates inflammatory, signaling and adhesion proteins in the BBB. Our results show that misfolded tau initiates signaling events leading to glial activation. Activated glial cells, in turn, aggravate transmigration of peripheral blood cells into the brain parenchyma.

The current study highlighted the role of tau protein in BBB changes observed in tauopathies. Neuroimmune events could be crucial components of neurofibrillary degeneration in the disease´s pathology. Our data suggest that tau protein has a prominent role in regulating, perpetuating inflammation, and thus exacerbating the disease pathology.

 

Source:

http://doi.org/10.1371/journal.pone.0217216

 

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