A number of evidences indicates oxidative stress as a relevant pathogenic factor in Alzheimer's disease (AD) and mild cognitive impairment (MCI). Considering its recognized major genetic risk factors in AD, apolipoprotein (APO E) has been investigated in several experimental settings regarding its role in the process of reactive oxygen species (ROS) generation. The aim of this work has been to evaluate possible relationships between APO E genotype and plasma levels of selected oxidative stress markers in both AD and MCI patients. APO E genotypes were determined using restriction enzyme analysis. Plasma levels of oxidative markers, advanced oxidation protein products, iron-reducing ability of plasma and, in MCI, activity of superoxide dismutases were evaluated using spectrophotometric analysis. We found, compared to controls, increased levels of oxidized proteins and decreased values of plasma-reducing capacity in both AD patients (p < 0.0001) and MCI patients (p < 0.001); the difference between AD and MCI patients was significant only for plasma-reducing capacity (p < 0.0001), the former showing the lowest values. Superoxide dismutase activity was reduced, although not at statistical level, in MCI compared with that in controls. E4 allele was statistically associated (p < 0.05) with AD patients. When comparing different APO E genotype subgroups, no difference was present, as far as advanced oxidation protein products and iron-reducing ability of plasma levels were concerned, between E4 and non-E4 carriers, in both AD and MCI; on the contrary, E4 carriers MCI patients showed significantly decreased (p < 0.05) superoxide dismutase activity with respect to non-E4 carriers. This study, in confirming the occurrence of oxidative stress in AD and MCI patients, shows how it can be related, at least for superoxide dismutase activity in MCI, to APO E4 allele risk factor.

The role of exercise in Amyotrophic lateral sclerosis (ALS) pathogenesis is controversial and unclear. Exercise induces a pleiotropic adaptive response in skeletal muscle, largely through the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a transcriptional coactivator that regulates mitochondrial biogenesis and antioxidant defense mechanisms. It has been suggested that a Gly482Ser substitution in PGC-1α has functional relevance in human disorders and in athletic performance. To test this hypothesis, we examined the genotype distribution of PGC-1α Gly482Ser (1444 G > A) in ALS patients to evaluate whether or not the minor serine-encoding allele 482Ser is involved in oxidative stress responses during physical exercise. We genotyped 197 sporadic ALS patients and 197 healthy controls in order to detect differences in allelic frequencies and genotype distribution between the two groups. A total of 74 ALS patients and 65 controls were then comparatively assessed for plasmatic levels of the oxidative stress biomarkers, advanced oxidation protein products, ferric reducing ability and thiol groups. In addition a subgroup of 35 ALS patients were also assessed for total SOD and catalase plasmatic activity. Finally in 28 ALS patients we evaluated the plasmatic curve of the oxidative stress biomarkers and lactate during an incremental exercise test. No significant differences were observed in the genotype distribution and allelic frequency in ALS patients compared to the controls. We found significant increased advanced oxidation protein products (p < 0.001) and significant decreased ferric reducing ability (p < 0.001) and thiol groups (p < 0.001) in ALS patients compared to controls. When comparing different genotypes of PGC-1α, no relation between Gly482Ser polymorphism and oxidative stress biomarker levels was detected in resting conditions. On the other hand, when considering exercise performance, lactate levels were significantly higher (between p < 0.01 and p < 0.001) and greater protein oxidative products were found in AA (Ser482Ser) compared to GG (Gly482Gly) and GA (Gly482Ser) ALS patients. Our findings highlight the importance and confirm the involvement of oxidative stress in ALS pathogenesis. Although not associated with 1444 G > A SNP, ALS patients with Gly482Ser allelic variant show increased exercise-related oxidative stress. This thus highlights the possible role of this antioxidant defense transcriptional coactivator in ALS.

Oxidative stress involvement has been strongly hypothesized among the possible pathogenic mechanisms of motor neuron degeneration in amyotrophic lateral sclerosis (ALS). The intracellular redox balance is finely modulated by numerous complex mechanisms critical for cellular functions, among which the nuclear factor erythroid-derived 2-like 2 (NFE2L2/Nrf2) pathways. We genotyped, in a cohort of ALS patients(n=145)and healthy controls(n=168), three SNPs inNrf2gene promoter: −653 A/G, −651 G/A, and −617 C/A and evaluated, in a subset(n=73)of patients, advanced oxidation protein products (AOPP), iron-reducing ability of plasma (FRAP), and plasma thiols (-SH) as oxidative damage peripheral biomarkers.Nrf2polymorphisms were not different among patients and controls. Increased levels of AOPP(P<0.05)and decreased levels of FRAP(P<0.001)have been observed in ALS patients compared with controls, but no difference in -SH values was found. Furthermore, no association was found between biochemical markers of redox balance andNrf2polymorphisms. These data confirm an altered redox balance in ALS and indicate that, while being abnormally modified compared to controls, the oxidative stress biomarkers assessed in this study are independent from the −653 A/G, −651 G/A, and −617 C/ANrf2SNPs in ALS patients.