Impact of ApoE Polymorphism and Physical Activity on Plasma Antioxidant Capability and Erythrocyte Membranes

Abstract

The allele epsilon 4 (ε4) of apolipoprotein E (ApoE) is the strongest genetic risk factor for Alzheimer's disease (AD). ApoE protein plays a pivotal role in the synthesis and metabolism of amyloid beta (Aβ), the major component of the extracellular plaques that constitute AD pathological hallmarks. Regular exercise is an important preventive/therapeutic tool in aging and AD. Nevertheless, the impact of physical exercise on the well-being of erythrocytes, a good model of oxidative stress and neurodegenerative processes, remains to be investigated, particularly depending on ApoE polymorphism. Herein, we evaluate the oxidative status, Aβ levels, and the membrane's composition of erythrocytes in a cohort of human subjects. In our hands, the plasma antioxidant capability (AOC), erythrocytes membrane fluidity, and the amount of phosphatidylcholine (PC) were demonstrated to be significantly decreased in the ApoE ε4 genotype and non-active subjects. In contrast, erythrocyte Aβ content and lipid peroxidation increased in ε4 carriers. Regular physical exercise was associated with an increased plasma AOC and membrane fluidity, as well as to a reduced amount of erythrocytes Aβ. Altogether, these data highlight the influence of the ApoE genotype on erythrocytes' well-being and confirm the positive impact of regular physical exercise.

Keywords: ApoE ε4; amyloid beta; cellular membrane; erythrocytes; oxidative stress; physical activity.

Figure 1

Plasma AOC levels, erythrocyte Aβ accumulation, and plasma lipid peroxidation amount in active and non-active subjects depending on ApoE genotype. (a) Plasma AOC depends on ApoE genotype and increases with physical activity. High TOSC values are associated with elevated antioxidant capacity. (b) Aβ accumulation in erythrocytes is influenced by ApoE genotype and decreases with physical activity. (c) Lipid peroxidation is higher in ApoE ε4 carriers and is not modulated by physical activity. The data are presented as the mean value ± S.D. and are representative of three independent experiments (n = 3). Difference among groups were assessed by One-way ANOVA. P-values were adjusted with Sidak’s multiple comparison test: * P < 0.05, ** P < 0.01, *** P < 0.001, **** P < 0.0001 between the indicated subgroups.

Figure 2

Membrane composition and membrane fluidity in active and non-active subjects depending on ApoE genotype. (a,b) The amount of PC and PE is differently affected by ApoE polymorphism and physical activity. The results are expressed in terms of concentration of PC (μM) and PE (μM). (c) Membrane fluidity of erythrocytes is negatively affected by ApoE ε4 polymorphism, but positively modulated by physical exercise. By determining the ratio of the fluorescence of excimer (Ex/Em = 350/470 nm) to the fluorescence of monomer (Ex/Em = 350/370 nm), quantitative monitoring of membrane fluidity is achieved. Elevated levels of the excimer to monomer fluorescence ratio (Ie/Im) reveal a higher membrane fluidity. The data are presented as the mean value ± S.D. and are representative of three independent experiments (n = 3). Differences among groups were assessed by one-way ANOVA. P-values were adjusted with Sidak’s multiple comparison test: * P < 0.05, ** P < 0.01, **** P < 0.0001 between the indicated subgroups.

Figure 3

Correlation between plasma and erythrocytes well-being parameters. Correlation analysis between erythrocytes Aβ (a) or lipid peroxidation (b) and plasma AOC. (c) Correlation analysis between PE and age. Correlation analysis between plasma AOC (d), Aβ (e), or PE concentration (f) and Borg scale. Correlation between variables was determined by simple linear regression analysis, using the StatView program (Abacus Concepts, Inc., SAS Institute, Cary, NC). P and R² values obtained for each correlation are reported in the respective panel.

Figure 4

Multiple linear regression analysis in ε4-non carriers and ε4 carriers. The analysis was used to assess the relationship between erythrocytes Aβ concentration and physical activity level in ε4 carriers and non-ε4 carriers.

Figure 5

Modulation of the Aβ contents, oxidative status, and membrane’s composition of erythrocytes by ApoE polymorphism and physical activity. The presence of the ApoE ε4 genotype enhances Aβ levels and lipid peroxidation, and decreases plasma AOC, membrane fluidity, and PC amount in erythrocytes. Regular physical activity counteracts the negative effects exhibited by the ε4 genotype on Aβ levels, plasma AOC, and membrane fluidity.