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Volume 6, Issue 1, February Issue - 2018, Pages:220-229

Authors: Ohoud A. Alomari, Taha A.Kumosani, Archana P. Iyer, EtimadA. Huwait, Mohammed S. Bamaga, Naglaa M. Salim, Charles G. Glabe
Abstract: To determine the possible associations between antioxidant serum markers and apolipoprotein E (APOE) genotypes in an elderly demented Saudi population.
There were 80 subjects included in this study classified according to cognitive function as two groups control and demented patients. Antioxidant capacity and lipid peroxidation were measured using spectrophotometric analysis. APOE genotypes were determined using restriction enzyme analysis. Correlations of serum levels of antioxidant capacity and lipidperoxidation with APOE genotypes were assessed. Serum antioxidant capacity was significantly reduced in patients group in comparison to the control (p-value= 0.0125< 0.05). Also, lipid peroxidation level showed significantly higher concentration on patient compared to control group (p-value=0.0167?0.05). For APOE, three alleles (E2, E3 and E4) and four genotypes (E2/3, E3/3, E3/4 and E4/4) were identified in present study. There was a significant different between alleles and genotypes distribution in the study groups as the frequency of E4 was higher in the subjects with dementia compare toin control (p-value=0.0168?0.05) and (p-value=0.0447?0.05), respectively. However, no association was found between APOE status and serum levels of antioxidant capacity and lipid peroxidation. In conclusion, no correlation between antioxidant capacity or lipid peroxidation levels and APOE genotypes. They are independent risk factors for dementia in the Saudi population.
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Full Text: 1 Introduction Inrecent years, healthcare services are improved that lead to increase in longevity and life expectancy. Dementia is not considered as a normal part of aging, but its prevalence become more common among an elderly population (Prince et al., 2013; Castro-Chavira et al., 2015). Dementia is an acquired cognitive impairment syndrome with slow progression that can be caused by a range of diseases and injuries to the brain as neurocognitive disorder (American Psychiatric Association, 2013; Thakur, 2015; Chen et al., 2016). It is  characterized by progressive loss of cognitive and intellectual functions, especially memory and behavioral disabilities that interferes with a person’s daily life (World Health Organization, 2012; Alzheimer's Association, 2017). Causes of dementia can vary, depending on the types of brain changes that may be taking place and there are manygenetic, lifestyle, vascular risk factors including in its pathogenesis. The most common subtype of dementia is Alzheimer's disease and other types include Vascular dementia, Lewy body dementia and Frontotemporal dementia (World Health Organization, 2012; Alzheimer's Association, 2017). However, it is common for people to have these pathologies together as mixed dementia (Jellinger, 2007; Lee, 2011; Castro-Chavira et al., 2015). In the case of most progressive dementia there is no known cures available (Williams et al., 2010; Lundkvist et al., 2014; Alzheimer's Association, 2017).Though, there are multiple pharmacological and non-pharmacological treatments that have been proven to slow disease progression and treat symptoms (Rosini et al., 2014; Jedenius et al., 2015; D’Onofrio et al., 2016; Alzheimer's Association, 2017). The genetic aspects have been indicated to play an important role in the dementia development. The different subtypes of dementia have different structural genomics (Ferencz & Gerritsen, 2015). For example, Alzheimer's disease has more than 200 genes that might be involved in its pathogenesis (Cacabelos, 2008). In general, only apolipoprotein E4 gene is consistent between studies as the strongest genetic risk factor linked tomost common dementia subtype in various populations (Harold et al., 2009;Percy et al., 2014; Alzheimer's Association, 2017). The human apolipoprotein E (APOE) is a 299 amino acid glycoprotein that plays a key role in lipid transport and lipoprotein metabolism through both the vascular and  nervous systems  by binding to members of the low-density lipoprotein receptor family (Bu, 2009). The APOE gene is mapped to chromosome 19 which consists of four exons and three introns. The structural gene locus for APOE is polymorphic having three common different alleles APOE2 (cys112, cys158), APOE3 (cys112, arg158) and APOE4 (arg112, arg158). This amino substitution results in not only structural differences, but also physiologic differences such as their binding affinity for specific lipoprotein receptors, antioxidant properties, inflammatory responses and neuronal processes such as development and plasticity. Additionally, each of the APOE alleles is associated with differing risks of specific diseases (Mahley et al., 2006; Frieden & Garai, 2012; Liu et al., 2013). The E2, E3 and E4 alleles have a world-wide frequency of 8.4%, 77.9% and 13.7%, respectively (Riddell et al., 2008; Holtzman et al., 2012; Kang et al., 2016). There are three homozygous (E4/4, E3/3 and E2/2) and three heterozygous (E2/4, E3/4 and E2/3) genotype. The prevalence of APOE alleles and genotypes in Saudi population was closed to other population. A study on healthy unrelated Saudi subjects observed that the allelic frequencies of APOE were 79% for E3, 15% for E4 and 6% for E2 and five genotypes were detected (E3/E3, E4/E4, E2/E3, E2/E4 and E3/E4) with prevalence as percentage 63, 2.5, 8.5,1 and 25, respectively (Awad & El-Tarras, 2011) The APOE3 is most common and considered with normal lipid metabolism. However, APOE2 and APOE4 isoforms are related to abnormal lipid metabolism and associated with risk of many diseases. The APOE4 has been presented more harmful effects in the brain as it associated with neuronal mitochondrial dysfunction, decrease GABAergic interneuron selectivity, greater neuronal inflammation, less efficient neuronal repair, blood brain barrier (BBB) dysfunction, Aβ accumulation, reduction in cerebral blood flow and hypoxia (Zlokovic, 2011; Leduc et al., 2011; Ringman et al., 2012; Villeneuve et al., 2014). The frequency of the E4 allele is dramatically increased risk factor of most common form of dementia while the E2 allele being protective relative to the prevalent E3 allele (Corder et al., 1993; Dewji & Singer, 1996; Huang, 2010; Liu et al., 2013; Vos et al., 2013). Also, APOE4 carriers develop dementia 8–20 years earlier than non-carriers (Bertram & Tanzi, 2008; Verghese et al., 2011; Mahley & Huang, 2012; Panza et al., 2012). The APOE4 has been extensively studied in major subtypes of dementia including Alzheimer’s disease, mild cognitive impairment, vascular dementia diseases, Lewy body disease and frontotemporal dementia, however most studies have failed to report associations between APOE4 and susceptibility to Parkinson's disease and PD-associated dementia (Rubino et al., 2013; Zhou et al., 2014; Wang et al., 2014; Rohn, 2014; Bras et al., 2014; Walker et al., 2015; Yan et al., 2016; Chen et al., 2016). On the other hand, increasing evidence demonstrates that oxidative stress causes damage to cell function with aging and it is also involved in a number of age-related neurodegenerative disorders such as dementia (Niedzielska et al., 2016). In some circumstances the production of reactive oxygen species and reactive nitrogen species can exceed the endogenous antioxidant ability to destroy them and an oxidative imbalance occurs (Pham-Huy et al., 2008; Halliwell & Gutteridge, 2015). This event results in cellular oxidative stress and subsequent molecular oxidative damage, which can translate into altered cellular functions and as final result, cell death (Halliwell & Gutteridge, 2015). The cerebral tissue is very prone to oxidative imbalance because it is very rich in polyunsaturated fatty acids (PUFAs), has a high metabolic oxidative rate and content of transition metals which together act as potent prooxidants. In addition to brain insufficient antioxidant defines. Depending on the substrate attacked by the free radicals, oxidative stress will manifest as protein, DNA and  RNA oxidation or lipid peroxidation (Friedman, 2011). Increase in oxidation markers and decrease in antioxidant markers in blood, cerebrospinal fluid and in postmortem brain samples of patients with dementia are reported in many studies (Cristalli et al., 2012; Popa-Wagner et al., 2013; Schrag et al., 2013; Chang et al., 2014;  Niedzielska et al., 2016). The association between APOE genotype and the cellular stress response in dementia patients yielded inconsistent results. While some studies have shown that APOE4 is positively associated with markers of oxidative stress and negatively associated with antioxidant defense markers compared to APOE3 and APOE2 (Chico et al., 2013; Dose et al., 2016). Non significant differences was reported between the APOE isoforms and specific antioxidative properties by Zito et al. (2013) and López-Riquelme et al. (2016). The overall purpose of this research is to evaluate the possible relationship between APOE genotype and serum level of antioxidant in Saudi patients with dementia of different types. 2 Methods and materials 2.1 Subjects Eighty elderly Saudi subjects included in this research. They were classified into two groups viz., (i) Control group was recruited from out-patient sections of the Department of Laboratory, Alhada Armed Force Hospital in Taif region (ii) another group was patients with dementia were recruited from theHome Visit Unit, Prince Mansour Military Hospital in Taif region, Saudi Arabia from January to May 2017. The diagnosis of mild, moderate or severe dementia accomplished by a geriatric consultant based on physical examination and neurological tests. Each group has (20 Females, 20 Males) totally 40 subjects with onset age of 65 years or older. Written consents were obtained from subjects or their caregivers. Unit of Medical Research Committee in Armed Forces Hospitals approved this study. The experimental work of this study was conducted at the Experimental Biochemistry Unit and Central Labs, King Fahd Medical Research Centre (KFMRC)‚ Jeddah‚ Saudi Arabia. 2.2 Blood Collections Blood collections were performed according to the standard process. Whole blood samples were drawn from the antecubital vein of patients with dementia and age-matched control. Blood sample were collected in gel serum separation tubes (SST) for antioxidant capacity and lipid peroxidation tests and into (K2EDTA) anticoagulated tubes for DNA extraction.Collected blood samples were kept in a thermal insulated box along with packs of ice through transport. The yellow gel tubes were allowed to clot at room temperature for 30 minutes and centrifuged at 2500 xg for 10 min at 4?C. Then, serum supernatant was removed and divided into 0.5 ml aliquots and stored at around -80?C until analysis. The Lavender tubes were used for DNA extraction stored in refrigerator at 4?C. 2.3 Antioxidant Capacity and Lipid peroxidation Assessment Ferric Reducing Antioxidant Power (FRAP) as antioxidant capacity indicator and Thiobarbituric Acid Reactive Substances (TBARS) concentrations as one of final product of lipid peroxiation were measured according to kitmanufacturer protocols. FRAP Aassy Kit (Cellbiolab,USA, Cat. no. STA-859) and TBARS Assay Kit (Caymanchem USA, Cat. no. 10009055). 2.4 Measurement of Antioxidant capacity Ferric Reducing Antioxidant Power (FRAP) assay is redox-dependent colorimetric assay. The principle based on the highly-cited work of Benzie & Strain(1996) which antioxidants present within the sample donated electrons to Ferric iron (Fe3+) which lead to reduced them to the ferrous form (Fe2+). The iron colorimetric probe complex developed a dark blue color produced upon reduction, which can be measured at 540-600 nm (Benzie & Strain, 1996). 2.5 Measurement of Lipid Peroxiation A well-established method for screening and monitoring lipid peroxidation is the measurement of Thiobarbituric Acid Reactive Substances (TBARS) which are naturally present in biological samplesand itsreported in malonaldehyde (MDA) equivalents, a compound that results from the decomposition of polyunsaturated fatty acid lipid peroxides.In the presence of heat and acid, MDA in the samples was reacted with TBA to produce a colored end product which can be measured calorimetrically at wavelength 530-540 nm. 2.6 DNA Extraction Genomic DNA was extracted from whole blood samplesusing Gene JET Whole Blood Genomic DNA Purification Mini Kit (Thermo Scientific, USA, Cat. no. K0782). The extracted DNA was stored at -20?C for PCR amplification. Concentration and purity of the extracted DNA was calculated automatically by Nanodrop2000c instrument from Thermo Scientific (USA). 2.7 Polymerase chain reaction For Polymerase Chain Reaction (PCR), the reactions were prepared using GoTaq(R)Green PCR Master Mix (Promega, USA, Cat. no. M7122). The primers were developed from Macrogen. The forward primer was (5'-ACA GAA TTC GCC CCG GCC TGG TAC AC-3') and the reverse one was (5'-TAA GCT TGG CAC GGC TGT CCA AGG A-3’)as described by Emi et al.(1988). The reaction mix (50µl) contained 2X reaction buffer, 4µM MgCl2, 4µM deoxyribonucleoside triphosphates, 0.2µM of each primer, 0.45 U Taq DNA polymerase, 0.1 µM of Dimethyl Sulfoxide (DMSO) and 10-30 ng of DNA template. The total reaction volume was made up to 50µl with nuclease free water. The amplification conditions consisted of an initial denaturation at 95?C for 1 min, 35 cycles of denaturation at 95 ?C for 1 min, an annealing at 65 ?C for 1 min and an extension at 72 ?C for 1 min, followed by a final extension at 72?C for 5 min and ended at hold at 4?C. To verify PCR product, 2% agarose ethidium bromide stained gel was used. 2.8 Genotyping of Apolipoprotein E     Table1 Biochemical Characteristics of Control and Dementia  
Parameters Non-Demented Mean ± SD Demented Mean ± SD ????1 ????2 ????3   Female n= (20) Malen= (20) Female n=(20) Male n= (20)   Age (years) 76.67±2.64 78.46±5.68 78.61± 5.23 81.35±6.93 0.2826 0.1813 0.0683 (FRAP) Assay Iron (II) Concentration (µM) 199.79±58.74 189.57± 84.75 164.81±55.12 155.01±35.81 0.6601 0.5087 0.0125* SUM 194.68±72.16 159.91±46.15   (TBARS) Assay MDA Concentration(µM) 7.97±3.80 9.02±3.21 13.10±6.43 9.26±4.95 0.3516 0.0413* 0.0167* SUM 8.49±3.51 11.18±5.99  
*  Significant difference; ????1 Value for female and male Control group; ????

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