Nitrosative stress, cellular stress response, and thiol homeostasis in patients with Alzheimer's disease.
Alzheimer's disease (AD) is a neurodegenerative disorder with cognitive and memory decline, personality changes, and synapse loss. Increasing evidence indicates that factors such as oxidative and nitrosative stress, glutathione depletion, and impaired protein metabolism can interact in a vicious cycle, which is central to AD pathogenesis. In the present study, we demonstrate that brains of AD patients undergo oxidative changes classically associated with a strong induction of the so-called vitagenes, including the heat shock proteins (HSPs) heme oxygenase-1 (HO-1), HSP60, and HSP72, as well as thioredoxin reductase (TRXr). In inferior parietal brain of AD patients, a significant increase in the expression of HO-1 and TRXr was observed, whereas HO-2 expression was decreased, compared with controls. TRHr was not increased in AD cerebellum. Plasma GSH was decreased in AD patients, compared with the control group, and was associated with a significant increase in oxidative stress markers (i.e., GSSG, hydroxynonenal, protein carbonyl content, and nitrotyrosine). In AD lymphocytes, we observed an increased expression of inducible nitric oxide synthase, HO-1, Hsp72, HSP60, and TRXr. Our data support a role for nitrative stress in the pathogenesis of AD and indicate that the stress-responsive genes, such as HO-1 and TRXr, may represent important targets for novel cytoprotective strategies.
Calabrese
Vittorio
V
Department of Chemistry, Biochemistry, & Molecular Biology Section, Faculty of Medicine, University of Catania, Catania, Italy. calabres@mbox.unict.it
Sultana
Rukhsana
R
Scapagnini
Giovanni
G
Guagliano
Eleonora
E
Sapienza
Maria
M
Bella
Rita
R
Kanski
Jaroslaw
J
Pennisi
Giovanni
G
Mancuso
Cesare
C
Stella
Anna Maria Giuffrida
AM
Butterfield
D A
DA
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D005260:Female; D006706:Homeostasis; D006801:Humans; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism*; D015538:Nitrosation; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D026361:Reactive Nitrogen Species / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013438:Sulfhydryl Compounds / Q000378:metabolism*
D015415:Biomarkers; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D013438:Sulfhydryl Compounds; D009569:Nitric Oxide