NOX activity is increased in mild cognitive impairment.
This study was undertaken to investigate the profile of NADPH oxidase (NOX) in the clinical progression of Alzheimer's disease (AD). Specifically, NOX activity and expression of the regulatory subunit p47phox and the catalytic subunit gp91phox was evaluated in affected (superior and middle temporal gyri) and unaffected (cerebellum) brain regions from a longitudinally followed group of patients. This group included both control and late-stage AD subjects, and also subjects with preclinical AD and with amnestic mild cognitive impairment (MCI) to evaluate the profile of NOX in the earliest stages of dementia. Data show significant elevations in NOX activity and expression in the temporal gyri of MCI patients as compared with controls, but not in preclinical or late-stage AD samples, and not in the cerebellum. Immunohistochemical evaluations of NOX expression indicate that whereas microglia express high levels of gp91phox, moderate levels of gp91phox also are expressed in neurons. Finally, in vitro experiments showed that NOX inhibition blunted the ability of oligomeric amyloid beta peptides to injure cultured neurons. Collectively, these data show that NOX expression and activity are upregulated specifically in a vulnerable brain region of MCI patients, and suggest that increases in NOX-associated redox pathways in neurons might participate in the early pathogenesis of AD.
Bruce-Keller
Annadora J
AJ
Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana 70808, USA. annadora.bruce-keller@pbrc.edu
Gupta
Sunita
S
Parrino
Taryn E
TE
Knight
Alecia G
AG
Ebenezer
Philip J
PJ
Weidner
Adam M
AM
LeVine
Harry
H
Keller
Jeffrey N
JN
Markesbery
William R
WR
D000203:Activities of Daily Living; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured / Q000187:drug effects / Q000201:enzymology; D002531:Cerebellum / Q000201:enzymology; D003072:Cognition Disorders / Q000201:enzymology* / Q000473:pathology; D018450:Disease Progression; D004790:Enzyme Induction; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D017628:Microglia / Q000201:enzymology; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D009474:Neurons / Q000201:enzymology / Q000473:pathology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D013702:Temporal Lobe / Q000201:enzymology* / Q000473:pathology
D016229:Amyloid beta-Peptides; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C056558:CYBB protein, human; C500593:Cybb protein, rat; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1