title: Enhancement of beta-amyloid peptide A beta(1-40)-mediated neurotoxicity by glutamine synthetase.
abstract: The beta-amyloid peptide (A beta), a main constituent in both senile and diffuse plaques in Alzheimer's disease brains, was previously shown to be neurotoxic and to be able to interact with several macromolecular components of brain tissue. Previous investigations carried out in our laboratory demonstrated free radical species formation in aqueous solutions of A beta(1-40) and its C-end fragment, A beta(25-35). Toxic forms of A beta rapidly inactivate the oxidation-sensitive cytosolic enzyme glutamine synthetase (GS). In this regard, we suggested and subsequently demonstrated that A beta radicals can cause an oxidative damage of cell proteins and lipids resulting in disruption of membrane functions, enzyme inactivation, and cell death. Because GS can be a substrate for A beta-derived oxidizing species, the present study was conducted to determine if GS could protect against A beta neurotoxicity. In contrast to this initial hypothesis, we here report that GS significantly enhances the neurotoxic effects of A beta(1-40). The A beta-mediated inactivation of GS was found to be accompanied by the loss of immunoreactive GS and the significant increase of A beta(1-40) neurotoxicity.
authors.affiliation: Department of Pharmacology, University of Kentucky, Lexington 40506, USA.
authors.lastname: Aksenov MYu
authors.forename: M V
authors.initials: MV
authors.lastname: Aksenova
authors.forename: M E
authors.initials: ME
authors.lastname: Harris
authors.forename: K
authors.initials: K
authors.lastname: Hensley
authors.forename: D A
authors.initials: DA
authors.lastname: Butterfield
authors.forename: J M
authors.initials: JM
authors.lastname: Carney
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D004578:Electron Spin Resonance Spectroscopy; D004789:Enzyme Activation / Q000187:drug effects; D005974:Glutamate-Ammonia Ligase / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009498:Neurotoxins / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats
chemical_list: D016229:Amyloid beta-Peptides; D009498:Neurotoxins; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D005974:Glutamate-Ammonia Ligase