Expression and activities of aldo-keto oxidoreductases in Alzheimer disease.
A reactive intermediate generated by lipid peroxidation, 4-hydroxy-2-nonenal (HNE), has received considerable attention as a potential effector of oxidative damage and Abeta peptide-mediated neurotoxicity in Alzheimer disease (AD). However, little is known about aldo-keto oxidoreductases, a group of enzymes that constitute a major detoxifying pathway for HNE and related reactive aldehydes in human brain. We have determined the regional, cellular, and class distribution in human brain of the 4 major aldo-keto oxidoreductases that detoxify HNE: aldehyde dehydrogenase (ALDH): aldose reductase; aldehyde reductase: and alcohol dehydrogenase (ADH). Of these 4 enzymes, only ALDH and aldose reductase were expressed in cerebral cortex. hippocampus, basal ganglia, and midbrain: all 4 enzymes were present in cerebellum. In cerebrum and hippocampus, aldose reductase was localized to pyramidal neurons and mitochondrial class 2 ALDH was localized to glia and senile plaques. ALDH, but not aldose reductase, activity was significantly increased in temporal cortex from patients with AD compared to age-matched controls. These results suggest that in brain regions involved in AD, neurons and glia utilize different mechanisms to detoxify HNE, and that increased ALDH activity is a protective response of cerebral cortex to AD.
Picklo
M J
MJ
Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Olson
S J
SJ
Markesbery
W R
WR
Montine
T J
TJ
D000426:Alcohol Dehydrogenase / Q000378:metabolism; D000444:Aldehyde Dehydrogenase / Q000096:biosynthesis*; D000449:Aldehyde Reductase / Q000096:biosynthesis* / Q000378:metabolism; D000447:Aldehydes / Q000378:metabolism; D000544:Alzheimer Disease / Q000201:enzymology* / Q000473:pathology; D000818:Animals; D000918:Antibody Specificity; D001921:Brain / Q000201:enzymology* / Q000473:pathology; D004789:Enzyme Activation; D006801:Humans; D015151:Immunoblotting; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009457:Neuroglia / Q000201:enzymology / Q000473:pathology; D009928:Organ Specificity; D017966:Pyramidal Cells / Q000201:enzymology / Q000473:pathology
D000447:Aldehydes; D000426:Alcohol Dehydrogenase; D000449:Aldehyde Reductase; D000444:Aldehyde Dehydrogenase; C027576:4-hydroxy-2-nonenal