Type-dependent oxidative damage in frontotemporal lobar degeneration: cortical astrocytes are targets of oxidative damage

J Neuropathol Exp Neurol. 2008 Dec;67(12):1122-36. doi: 10.1097/NEN.0b013e31818e06f3.

Abstract

Oxidative injury and stress responses are common features of many neurodegenerative diseases. To assess oxidative stress responses in frontotemporal lobar degeneration (FTLD), we identified increased 4-hydroxynonenal (HNE) adducts using gel electrophoresis and Western blotting in frontal cortex samples in 6 of 6 cases of FTLD with the P301L mutation in the tau gene (FTLD-tau), in 3 of 10 cases with tau-negative ubiquitin-immunoreactive inclusions, and in 2 of 3 cases associated with motor neuron disease. Selectively increased lipoxidation-derived protein damage associated with altered membrane unsaturation and fatty acid profiles was verified by mass spectrometry in FTLD-tau and FTLD associated with motor neuron disease. All FTLD-tau and most cases with increased HNE-positive bands had marked astrocytosis as determined by glial fibrillary acidic protein (GFAP) immunohistochemistry and increased GFAP expression on Western blotting; 2 FTLD cases with tau-negative ubiquitin-immunoreactive inclusions and with increased GFAP expression did not have increased HNE adducts. Bidimensional gel electrophoresis, Western blotting, in-gel digestion, and mass spectrometry identified GFAP as a major target of lipoxidation in all positive cases; confocal microscopy revealed colocalization of HNE and GFAP in cortical astrocytes, superoxide dismutase 1 in astrocytes, and superoxide dismutase 2 in astrocytes and neurons in all FTLD types. Thus, in FTLD, there is variable disease-dependent oxidative damage that is prominent in FTLD-tau, astrocytes are targets of oxidative damage, and GFAP is a target of lipoxidation. Astrocytes are, therefore, crucial elements of oxidative stress responses in FTLD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Aldehydes / metabolism
  • Astrocytes / metabolism*
  • Astrocytes / pathology
  • Biomarkers / analysis
  • Biomarkers / metabolism
  • Cerebral Cortex / metabolism*
  • Cerebral Cortex / pathology
  • Cerebral Cortex / physiopathology
  • Dementia / metabolism*
  • Dementia / pathology
  • Dementia / physiopathology
  • Glial Fibrillary Acidic Protein / metabolism
  • Gliosis / metabolism
  • Gliosis / pathology
  • Gliosis / physiopathology
  • Humans
  • Inclusion Bodies / metabolism*
  • Inclusion Bodies / pathology
  • Lipid Peroxidation / physiology
  • Male
  • Middle Aged
  • Nerve Tissue Proteins / metabolism*
  • Oxidative Stress / physiology*
  • Superoxide Dismutase / metabolism
  • Superoxide Dismutase-1
  • Ubiquitin / metabolism
  • tau Proteins / genetics

Substances

  • Aldehydes
  • Biomarkers
  • Glial Fibrillary Acidic Protein
  • Nerve Tissue Proteins
  • SOD1 protein, human
  • Ubiquitin
  • tau Proteins
  • Superoxide Dismutase
  • Superoxide Dismutase-1
  • superoxide dismutase 2
  • 4-hydroxy-2-nonenal