Deficiency of telomerase activity aggravates the blood-brain barrier disruption and neuroinflammatory responses in a model of experimental stroke

Bei Zhang, Lei Chen, Karin R. Swartz, Dennis Bruemmer, Sung Yong Eum, Wen Huang, Melissa Seelbach, Yean Jung Choi, Bernhard Hennig, Michal Toborek

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Epidemiology and genetic studies indicate that patients with telomere length shorter than average are at higher risk of dying from heart disease or stroke. Telomeres are located at the ends of eukaryotic chromosomes, which demonstrate progressive length reduction in most somatic cells during aging. The enzyme telomerase can compensate for telomere loss during cell replication. The present study sought to investigate the contribution of telomerase to stroke and blood-brain barrier (BBB) dysfunction. Telomerase reverse transcriptase knockout (TERT-/-) mice and littermate controls with normal TERT expression were subjected to a 24-hr permanent middle cerebral artery occlusion (pMCAO). The stroke outcomes were assessed in terms of neurological scores and infarct volumes. In addition, we evaluated oxidative stress, permeability across the BBB, and integrity of tight junctions in brain microvessels. Neurological testing revealed that TERT-/- mice showed enhanced deficits compared with controls. These changes were associated with a greater infarct volume. The expression of tight junction protein ZO-1 decreased markedly in ischemic hemispheres of TERT-/- mice. The brain microvessels of TERT -/- mice also were more susceptible to oxidative stress, revealing higher superoxide and lower glutathione levels compared with mice with normal TERT expression. Importantly, TERT deficiency potentiated the production of inflammatory mediators, such as tumor necrosis factor-α, interleukin-1β, and intercellular adhesion molecule-1, in the ischemic hemispheres of mice with pMCAO. Our study suggests that TERT deficiency can predispose to the development of stroke in an experimental model of this disease.

Original languageEnglish (US)
Pages (from-to)2859-2868
Number of pages10
JournalJournal of Neuroscience Research
Volume88
Issue number13
DOIs
StatePublished - Oct 1 2010

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Keywords

  • Blood-brain barrier
  • Cerebral microvessels
  • Stroke
  • Telomerase reverse transcriptase
  • Tight junction proteins

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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