Reduced early hypoxic/ischemic brain damage is associated with increased GLT-1 levels in mice expressing mutant (P301L) human tau

Brain Res. 2009 Jan 9:1247:159-70. doi: 10.1016/j.brainres.2008.10.022. Epub 2008 Nov 1.

Abstract

Mutations in tau proteins are associated with a group of neurodegenerative diseases, termed tauopathies. To investigate whether over-expressing human tau with P301L mutation also affects stroke-induced brain damage, we performed hypoxia/ischemia (H/I) in young adult P301L tau transgenic mice. Surprisingly, brain infarct volume was significantly smaller in transgenic mice compared to wild-type mice 24 h after H/I induction. TUNEL staining also revealed less brain apoptosis in transgenic mice following H/I. H/I resulted in a significant increase in tau fragments generated by caspase activation and a marked decrease in tau phosphorylation at residue T231 in cortex of wild-type but not transgenic mice. Activation of calpain and caspase-3 following H/I was also reduced in transgenic compared to wild-type mice, as reflected by lower levels of the specific spectrin breakdown products generated by calpain or caspase-3. Finally, basal levels of the glial glutamate transporter, GLT-1, were higher in brains of transgenic as compared to wild-type mice. These results support the idea that enhanced levels of GLT-1 in transgenic mice are responsible for reducing H/I-induced brain damage by decreasing extracellular glutamate accumulation and subsequent calpain and caspase activation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence / genetics
  • Animals
  • Apoptosis / genetics
  • Brain Infarction / genetics
  • Brain Infarction / metabolism*
  • Brain Infarction / physiopathology
  • Calpain / metabolism
  • Caspase 3 / metabolism
  • Cytoprotection / genetics
  • Excitatory Amino Acid Transporter 2 / metabolism*
  • Glutamic Acid / metabolism*
  • Humans
  • Hypoxia-Ischemia, Brain / genetics
  • Hypoxia-Ischemia, Brain / metabolism*
  • Hypoxia-Ischemia, Brain / physiopathology
  • In Situ Nick-End Labeling
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nerve Degeneration / genetics
  • Nerve Degeneration / metabolism*
  • Nerve Degeneration / physiopathology
  • Organ Culture Techniques
  • Up-Regulation / genetics
  • tau Proteins / chemistry
  • tau Proteins / genetics*

Substances

  • Excitatory Amino Acid Transporter 2
  • tau Proteins
  • Glutamic Acid
  • Calpain
  • Caspase 3