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.
Highlights
IntroductionServices SE provided support in the form of salaries for PM, AM, JH, MC, SJ and AK, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript
We examined if the transmigration of peripheral blood monocyte-derived macrophages (PB-MoM) across in vitro blood-brain barrier (BBB) model is mediated by adhesion molecules intracellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1)
Using transgenic rat model of tauopathy 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
Summary
Services SE provided support in the form of salaries for PM, AM, JH, MC, SJ and AK, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section
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