Human truncated tau is using a different mechanism from amyloid-β to damage the blood-brain barrier

Andrej Kovac, Monika Zilkova, Maria A. Deli, Norbert Zilka, Michal Novak

Research output: Contribution to journalArticle

29 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)897-906
Number of pages10
JournalJournal of Alzheimer's Disease
Volume18
Issue number4
DOIs
Publication statusPublished - 2009

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Keywords

  • Alzheimer's disease
  • Blood-brain barrier
  • Microglia
  • Truncated tau protein
  • Tumor necrosis factor-α (TNF-α)

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

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