Affiliations: [a] Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovak Republic | [b] Axon Neuroscience GmbH, Vienna, Austria | [c] Laboratory of Molecular Neurobiology, Institute of Biophysics, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary
Correspondence:
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Corresponding author: Michal Novak, MDV, PhD, Institute of Neuroimmunology, Slovak Academy of Sciences, Dubravska 9, 845 10 Bratislava, Slovak Republic. Fax: +421 2 5477 4276; E-mail: [email protected].
Abstract: Recent findings showed that vascular dysfunction is an integral part of Alzheimer's disease pathology. Increased microvascular permeability is mainly associated with cerebrovascular amyloid-β deposits. In contrast, little is known about the relationship between functional impairment of the blood-brain barrier and misfolded tau. In the present study, we examined whether human truncated tau is able to impair the blood-brain barrier in an in vitro model. We have found that truncated tau induced a very strong polarity-dependent effect in the rat blood-brain barrier model. When the tau was added to the upper compartment of the model containing endothelial cells (apical treatment), no effect was observed. However, the application of tau to the lower compartment (basolateral treatment), consisting of astrocyte-microglia culture, triggered significant decrease of transendothelial electrical resistance and increase of endothelial permeability for mannitol. Further, we found that truncated tau showed cytotoxic effects on astrocyte-microglia culture manifested by increased extracellular adenylate kinase levels. Molecular analysis of underlying mechanisms of tau-induced blood-brain barrier damage revealed the contribution of pro-inflammatory cytokine tumor necrosis factor-α and chemokine MCP-1 released from activated microglial cells. This study for the first time uncovers a novel toxic gain of function of misfolded tau that could contribute to the cerebral microvascular damage in human tauopathies.
