4-Hydroxyhexenal (HHE) impairs glutamate transport in astrocyte cultures

J Alzheimers Dis. 2012;32(1):139-46. doi: 10.3233/JAD-2012-120409.


Multiple studies show elevations of α,β-unsaturated aldehydic by-products of lipid peroxidation including 4-hydroxynonenal and acrolein in vulnerable brain regions of subjects throughout the progression of Alzheimer's disease (AD). More recently 4-hydroxyhexenal (HHE), a diffusible α,β-unsaturated aldehyde resulting from peroxidation of ω-3 polyunsaturated fatty acids, was shown to be elevated in the hippocampus/parahippocampal gyrus (HPG) of subjects with preclinical AD (PCAD) and in late stage AD (LAD). HHE treatment of primary rat cortical neuron cultures led to a time- and concentration-dependent decrease in survival and glucose uptake. To determine if HHE also impairs glutamate uptake, primary rat astrocyte cultures were exposed to HHE for 4 hours and glutamate transport measured. Results show subtoxic (2.5 μM) HHE concentrations significantly (p < 0.05) impair glutamate uptake in primary astrocytes. Immunoprecipitation of excitatory amino acid transporter-2 (EAAT-2), the primary glutamate transporter in brain, from normal control, mild cognitive impairment (MCI), PCAD, and LAD HPG followed by quantification of HHE immunolabeling showed a significant increase in HHE positive EAAT-2 in MCI and LAD HPG. Together these data suggest HHE can significantly impair glutamate uptake and may play a role in the pathogenesis of AD.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged, 80 and over
  • Aldehydes / pharmacology*
  • Alzheimer Disease / metabolism
  • Animals
  • Astrocytes / drug effects
  • Astrocytes / metabolism*
  • Biological Transport, Active / drug effects
  • Blotting, Western
  • Brain Chemistry / drug effects
  • Cells, Cultured
  • Cognitive Dysfunction / metabolism
  • Coloring Agents
  • Excitatory Amino Acid Transporter 2
  • Female
  • Glutamate Plasma Membrane Transport Proteins / metabolism
  • Glutamates / metabolism*
  • Humans
  • Immunoprecipitation
  • Lipid Peroxidation / drug effects
  • Male
  • Parahippocampal Gyrus / metabolism
  • Rats
  • Tetrazolium Salts
  • Thiazoles


  • Aldehydes
  • Coloring Agents
  • Excitatory Amino Acid Transporter 2
  • Glutamate Plasma Membrane Transport Proteins
  • Glutamates
  • SLC1A2 protein, human
  • Tetrazolium Salts
  • Thiazoles
  • 4-hydroxyhexenal
  • thiazolyl blue