Oxidative stress and reduced antioxidant defenses in peripheral cells from familial Alzheimer's patients.
We have measured the levels of typical end products of the processes of lipid peroxidation, protein oxidation, and total antioxidant capacity (TAC) in skin fibroblasts and lymphoblasts taken from patients with familial Alzheimer's disease (FAD), sporadic Alzheimer's disease (AD), and age-matched healthy controls. Compared to controls, the fibroblasts and lymphoblasts carrying amyloid precursor protein (APP) and presenilin-1 (PS-1) gene mutations showed a clear increase in lipoperoxidation products, malondialdehyde (MDA), and 4-hydroxynonenal (4-HNE). In contrast, the antioxidant defenses of cells from FAD patients were lower than those from normal subjects. Lipoperoxidation and antioxidant capacity in lymphoblasts from patients affected by sporadic AD were virtually indistinguishable from the basal values of normal controls. An oxidative attack on protein gave rise to greater protein carbonyl content in FAD patients than in age-matched controls. Furthermore, ADP ribosylation levels of poly(ADP-ribose) polymerase (PARP) nuclear substrates were significantly raised, whereas the PARP content did not differ significantly between fibroblasts carrying gene mutations and control cells. These results indicate that peripheral cells carrying APP and PS-1 gene mutations show altered levels of oxidative markers even though they are not directly involved in the neurodegenerative process of AD. These results support the hypothesis that oxidative damage to lipid, protein, and DNA is an important early event in the pathogenesis of AD.
Cecchi
Cristina
C
Department of Biochemical Sciences, University of Florence, Florence, Italy.
Fiorillo
Claudia
C
Sorbi
Sandro
S
Latorraca
Stefania
S
Nacmias
Benedetta
B
Bagnoli
Silvia
S
Nassi
Paolo
P
Liguri
Gianfranco
G
D000447:Aldehydes / Q000494:pharmacology; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry; D000975:Antioxidants / Q000494:pharmacology*; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005609:Free Radicals; D006801:Humans; D015151:Immunoblotting; D015227:Lipid Peroxidation; D008315:Malondialdehyde / Q000494:pharmacology; D009154:Mutation; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism
D000447:Aldehydes; D016229:Amyloid beta-Peptides; D000975:Antioxidants; D005609:Free Radicals; D008315:Malondialdehyde; D011065:Poly(ADP-ribose) Polymerases; C027576:4-hydroxy-2-nonenal; D010100:Oxygen