title: 4-Hydroxyhexenal (HHE) impairs glutamate transport in astrocyte cultures.
abstract: 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.
authors: Department of Chemistry, University of Kentucky, Lexington, KY, USA.
authors: Mark A
authors: MA
authors: Lovell
authors: Melissa A
authors: MA
authors: Bradley
authors: Shuling X
authors: SX
authors: Fister
mesh_terms: D000369:Aged, 80 and over; D000447:Aldehydes / Q000494:pharmacology*; D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D001693:Biological Transport, Active / Q000187:drug effects; D015153:Blotting, Western; D001923:Brain Chemistry / Q000187:drug effects; D002478:Cells, Cultured; D060825:Cognitive Dysfunction / Q000378:metabolism; D004396:Coloring Agents; D027342:Excitatory Amino Acid Transporter 2; D005260:Female; D050491:Glutamate Plasma Membrane Transport Proteins / Q000378:metabolism; D005971:Glutamates / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D020534:Parahippocampal Gyrus / Q000378:metabolism; D051381:Rats; D013778:Tetrazolium Salts; D013844:Thiazoles
chemical_list: D000447:Aldehydes; D004396:Coloring Agents; D027342:Excitatory Amino Acid Transporter 2; D050491:Glutamate Plasma Membrane Transport Proteins; D005971:Glutamates; C493397:SLC1A2 protein, human; D013778:Tetrazolium Salts; D013844:Thiazoles; C063409:4-hydroxyhexenal; C022616:thiazolyl blue