title: Human truncated tau is using a different mechanism from amyloid-beta to damage the blood-brain barrier.
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-beta 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-alpha 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.
authors.affiliation: Institute of Neuroimmunology, Slovak Academy of Sciences, 845 10 Bratislava, Slovak Republic.
authors.forename: Andrej
authors.initials: A
authors.lastname: Kovac
authors.forename: Monika
authors.initials: M
authors.lastname: Zilkova
authors.forename: Maria A
authors.initials: MA
authors.lastname: Deli
authors.forename: Norbert
authors.initials: N
authors.lastname: Zilka
authors.forename: Michal
authors.initials: M
authors.lastname: Novak
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000544:Alzheimer Disease / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D002199:Capillary Permeability; D018932:Chemokine CCL2 / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D017097:Electric Impedance; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D008297:Male; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D016875:tau Proteins / Q000502:physiology*
chemical_list: D016229:Amyloid beta-Peptides; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D018925:Chemokines; D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D016875:tau Proteins; D000263:Adenylate Kinase