Apolipoprotein E Polymorphism and Oxidative Stress in Human Peripheral Blood Cells: Can Physical Activity Reactivate the Proteasome System through Epigenetic Mechanisms?

Alzheimer’s disease (AD) is characterized by proteasome activity impairment, oxidative stress, and epigenetic changes, resulting in β-amyloid (Aβ) production/degradation imbalance. Apolipoprotein E (ApoE) is implicated in Aβ clearance, and particularly, the ApoE ε4 isoform predisposes to AD development. Regular physical activity is known to reduce AD progression. However, the impact of ApoE polymorphism and physical exercise on Aβ production and proteasome system activity has never been investigated in human peripheral blood cells, particularly in erythrocytes, an emerging peripheral model used to study biochemical alteration. Therefore, the influence of ApoE polymorphism on the antioxidant defences, amyloid accumulation, and proteasome activity was here evaluated in human peripheral blood cells depending on physical activity, to assess putative peripheral biomarkers for AD and candidate targets that could be modulated by lifestyle. Healthy subjects were enrolled and classified based on the ApoE polymorphism (by the restriction fragment length polymorphism technique) and physical activity level (Borg scale) and grouped into ApoE ε4/non-ε4 carriers and active/non-active subjects. The plasma antioxidant capability (AOC), the erythrocyte Aβ production/accumulation, and the nuclear factor erythroid 2-related factor 2 (Nrf2) mediated proteasome functionality were evaluated in all groups by the chromatographic and immunoenzymatic assay, respectively. Moreover, epigenetic mechanisms were investigated considering the expression of histone deacetylase 6, employing a competitive ELISA, and the modulation of two key miRNAs (miR-153-3p and miR-195-5p), through the miRNeasy Serum/Plasma Mini Kit. ApoE ε4 subjects showed a reduction in plasma AOC and an increase in the Nrf2 blocker, miR-153-3p, contributing to an enhancement of the erythrocyte concentration of Aβ. Physical exercise increased plasma AOC and reduced the amount of Aβ and its precursor, involving a reduced miR-153-3p expression and a miR-195-5p enhancement. Our data highlight the impact of the ApoE genotype on the amyloidogenic pathway and the proteasome system, suggesting the positive impact of physical exercise, also through epigenetic mechanisms.

LONG-COVID COGNITIVE IMPAIRMENT: COGNITIVE ASSESSMENT AND APOLIPOPROTEIN E (APOE) GENOTYPING CORRELATION IN A BRAZILIAN COHORT

Background: COVID-19 neurological manifestations were demonstrated during the pandemic, including cognitive impairment. Objectives: To determine the prevalence of cognitive and behavioral complaints (such as dementia, MCI or SCD) in a outpatient sample with recent SARS-COV2 infection. Specific: Evaluate the association of cognitive impairment with the presence of the polymorphism found in the APOE gene and with respiratory disease. Methodology: Observational, longitudinal, prospective clinical study. Inclusion criteria: patients with confirmed Covid-19. Patients are evaluated in an outpatient clinic. They are evaluated through a standardized attendance record, with somatic and cognitive neurological assessment. Cognitive assessment involves the application of cognitive (ACER, MMSE and CDR), functional (Pfeffer) and psychiatric (GDS or Beck) screening instruments, in addition to subsequent extensive neuropsychological assessment. In addition, APOE polymorphism is analysed. Preliminary. Results: To date, 191 patients and 11 controls were evaluated. The average age is 46.5 years, with 65.4% female, 79.16% with 8 or more years of schooling, in addition to 57.5% of the sample with cognitive complaints. Conclusions: The results so far in our study demonstrate that cognitive complaints are frequent in patients even in the chronic phase of the disease.

HOW COMMON IN POLISH POPULATION ARE GENOTYPES OF APOLIPOPROTEIN E WHICH PREDISPOSE TO ALZHEIMER’S DISEASE DEVELOPMENT?

Introduction Apolipoprotein E (ApoE) is a glycoprotein secreted mainly by hepatocytes. It’s involved in cell proliferation and cholesterol transport. ApoE is occurring primarily in 3 significant variants ε2, ε3 and ε4. It is coded by two genes what means the combination of two polymorphic alleles determines its genotype. ApoE-ε3/ε4 and -ε4/ε4 increase the risk of Alzheimer’s disease (AD) development several times compared to the general population. Early prevention can significantly slow down AD development and shorten its course. Aim The aim of this study was to check the distribution of ApoE gene among population from South Poland and compared results with previous study indicating allelic discrimination among random patients in research group. Material and methods In general we carried out genotyping polimorphism of ApoE. The process consisted of: 1. Colecting blood samples from patients, 2. Isolating DNA, 3. Preparating concentrations of DNA and checking it with spectrophotometer, 4. Allelic discrimination with fluorescent – labelled probes, 5. Genotyping of the ApoE polymorphism using Roche Lightcycler96 device. Study group consisted 830 subjects. 1660 determinations has been conducted. Results After expanding the research group by 81 patients it is shown that amount of carriers ApoE-ε2/ε4, ApoE-ε3/ε4 and ApoE-ε4/ε4 increases. The most numerous genotypes in research group are ApoE-ε2/ε2 and ApoE-ε3/ε3. Conclusions An upward trend in the relative numbers of carriers of genotype associated with a higher risk of developing AD has been noticed with the extension of research. Further research should be performed and the rese

Apolipoprotein E polymorphism and oxidative stress in human peripheral blood cells: can physical activity reactivate the proteasome system through epigenetic mechanisms?

Background Alzheimer’s Disease (AD) is characterised by proteasome activity impairment and oxidative stress, resulting in β-amyloid (Aβ) production/degradation imbalance. Apolipoprotein E (ApoE) is implicated in Aβ clearance, and ApoE ε4 isoform predisposes to AD development. Regular physical activity is known to reduce AD progression. However, the impact of ApoE polymorphism and physical exercise on Aβ production and proteasome system activity has never been investigated in human peripheral blood cells.Methods Healthy subjects were enrolled and classified based on the ApoE polymorphism (by the restriction fragment length polymorphism technique) and physical activity level (Borg Scale), dividing them in ApoE ε4/non-ε4 carriers and active/non-active subjects. The plasma antioxidant capability (AOC), the erythrocyte Aβ production/accumulation, and the nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated proteasome functionality were evaluated in all groups by chromatographic and immunoenzymatic assay, respectively. Moreover, epigenetic mechanisms were investigated considering the expression of the histone deacetylase 6, employing a competitive ELISA, and the modulation of two keys miRNAs (miR-153-3p and miR-195-5p), through miRNeasy Serum/Plasma Mini Kit.Results ApoE ε4 subjects showed a reduction in plasma AOC and an increase of the Nrf2 blocker, miR-153-3p, contributing to an enhancement of the erythrocyte concentration of Aβ. Physical exercise increased plasma AOC and reduced the amount of Aβ and its precursor, involving a reduced miR-153-3p expression and a miR-195-5p enhancement.Conclusions Our data highlight the impact of ApoE genotype on the amyloidogenic pathway and the proteasome system, and suggest the positive impact of physical exercise, also through epigenetic mechanisms.

The Association between Apolipoprotein E Polymorphism and Response to Statins in Group of Hyperlipidemic Patients

Background and Objectives: APOE has an important role in lipids metabolism, and in the variability in low density lipoprotein (LDL) response to statins treatment between individuals. In this study we aim to investigate the association between APOE polymorphism and response to statins in Jordanian hyperlipidemic patients at the diabetic clinic of Jordan University Hospital. Methods: One hundred and fifty two Jordanian Hyperlipidemic patients (52 males and 100 females) aged between 35-75 years were enrolled in this study. This study was approved by the Institutional Review Board (IRB) of Jordan University Hospital. The genotypes of the patients were identified by polymerase chain reaction followed by restriction fragment length polymorphism assay method (PCR-RFLP). Results and Conclusions: The study showed that there is an association between APOE polymorphism and response to statin therapy. Patients who were APOE ԑ4 carriers had lower response to statins compared to ԑ3 and ԑ2 carriers (p=0.002). In addition we found that there were no significant association between APOE polymorphism and LDL baseline (p=0.214). No significant differences in APOE genotypes distribution between males and females (p=0.06).No significant association was found between age and APOE genotypes (p=0.347). A genotype screening test for dyslipidemic Jordanian patients is recommended to choose the appropriate treatment decisions, dosage, and to recognize the potential side effects of the statin therapy.

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

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.