title: Elevation of AKR7A2 (succinic semialdehyde reductase) in neurodegenerative disease.
abstract: Elevated levels of oxidative stress or decreased antioxidant defense mechanisms may underlie the regionally increased oxidative damage to brain observed in many neurodegenerative disorders. Phase I detoxification pathways for reactive aldehydes generated from lipid peroxidation include aldehyde dehydrogenases, alcohol dehydrogenases and aldo-keto reductases (AKR). In the present study, we examined the cellular expression of AKR family member, succinic semialdehyde reductase (AKR7A2) that reduces toxic aldehydes as well as catalyzing the biosynthesis of the neuromodulator gamma-hydroxybutyrate (GHB). Our results show that in the cerebral cortex and hippocampus, AKR7A2 is primarily localized to glial cells, astrocytes and microglia. In the midbrain, AKR7A2 was found in glia and neuromelanin-containing neurons of the substantia nigra, and the periaqueductal gray. In sections of cerebral cortex and hippocampus from patients with AD and DLB, AKR7A2 immunoreactivity was elevated in reactive astrocytes and microglial cells. Furthermore, total AKR7A2 protein levels were elevated in the cerebral cortex of patients with AD versus control individuals. Our data suggest that reactive gliosis, as a response to injury, may affect GHB neuromodulatory pathways in neurodegenerative disease and elevate aldehyde detoxification pathways.
authors.affiliation: Department of Pathology, Vanderbilt University Medical Center, C3321-A Medical Center North, Nashville, TN 37232, USA. mpicklo@medicine.nodak.edu
authors.forename: M J
authors.initials: MJ
authors.lastname: Picklo
authors.forename: S J
authors.initials: SJ
authors.lastname: Olson
authors.forename: J D
authors.initials: JD
authors.lastname: Hayes
authors.forename: W R
authors.initials: WR
authors.lastname: Markesbery
authors.forename: T J
authors.initials: TJ
authors.lastname: Montine
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D001253:Astrocytes / Q000201:enzymology / Q000473:pathology; D001921:Brain / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D002451:Cell Compartmentation / Q000502:physiology; D002540:Cerebral Cortex / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D006624:Hippocampus / Q000196:embryology / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D006884:Hydroxybutyrate Dehydrogenase / Q000378:metabolism*; D007150:Immunohistochemistry; D020961:Lewy Body Disease / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D008297:Male; D017628:Microglia / Q000201:enzymology / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D009457:Neuroglia / Q000201:enzymology* / Q000473:pathology; D009474:Neurons / Q000201:enzymology* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012978:Sodium Oxybate / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D005680:gamma-Aminobutyric Acid; D012978:Sodium Oxybate; D006884:Hydroxybutyrate Dehydrogenase; C019416:4-hydroxybutyrate dehydrogenase