Roles of apolipoprotein E4 (ApoE4) in the pathogenesis of Alzheimer's disease: lessons from ApoE mouse models
ABSTRACT ApoE4 (apolipoprotein E4) is the major known genetic risk factor for AD (Alzheimer's disease). In most clinical studies, apoE4 carriers account for 65-80% of all AD cases, highlighting the importance of apoE4 in AD pathogenesis. Emerging data suggest that apoE4, with its multiple cellular origins and multiple structural and biophysical properties, contributes to AD in multiple ways either independently or in combination with other factors, such as Aβ (amyloid β-peptide) and tau. Many apoE mouse models have been established to study the mechanisms underlying the pathogenic actions of apoE4. These include transgenic mice expressing different apoE isoforms in neurons or astrocytes, those expressing neurotoxic apoE4 fragments in neurons and human apoE isoform knock-in mice. Since apoE is expressed in different types of cells, including astrocytes and neurons, and in brains under diverse physiological and/or pathophysiological conditions, these apoE mouse models provide unique tools to study the cellular source-dependent roles of apoE isoforms in neurobiology and in the pathogenesis of AD. They also provide useful tools for discovery and development of drugs targeting apoE4's detrimental effects.
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ABSTRACT: Alzheimer's disease (AD) is the most frequently diagnosed form of dementia resulting in cognitive impairment. Many AD mouse studies, using the methyl donor S-adenosylmethionine (SAM), report improved cognitive ability, but conflicting results between and within studies currently exist. To address this, we conducted a meta-analysis to evaluate the effect of SAM on cognitive ability as measured by Y maze performance. As supporting evidence, we include further discussion of improvements in cognitive ability, by SAM, as measured by the Morris water maze (MWM).PLoS ONE 10/2014; DOI:10.1371/journal.pone.0107756 · 3.53 Impact Factor
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ABSTRACT: Purpose The purpose of this study was to determine if antioxidant supplementation, moderate exercise, and the combination of both treatments could ameliorate cognitive performance in adult mice and whether the apolipoprotein E (APOE) genotype as well as sex could influence the functional outcomes of the treatments. Methods For a period of 16 weeks, separate groups of male and female mice expressing either the human APOE3 or APOE4 isoforms were fed either a control diet (NIH-31) or the control diet supplemented with vitamins E and C (1.12 IU/g diet α-tocopheryl acetate and 1.65 mg/g ascorbic acid). The mice were further separated into a sedentary group or a group that followed a daily exercise regimen. After 8 weeks on the treatments, the mice were administered a battery of functional tests including tests to measure cognitive and affective function. Results There was no effect of genotype or treatment on the learning performance in the Morris water maze. In the discriminated avoidance task, APOE4 mice performed better in learning the discrimination component of the task. Overall, exercise improved performance of APOE4 and APOE3 mice on various aspects of the active avoidance task. Antioxidant supplementation improved performance only in the APOE4 mice. On the test for anxiety, APOE4 mice spent more time in the open arms and supplementation with antioxidant reversed that effect. Conclusion Exercise was the most effective treatment at improving cognitive function in both genotypes and sex, while antioxidants seemed to be effective only in the APOE4. In young adult mice only non-spatial learning and memory were improved. The combination of the two treatments did not yield further improvement in cognition, and there was no antagonistic action of the antioxidant supplementation on the beneficial effects of exercise.Journal of Sport and Health Science 09/2014; 3(3). DOI:10.1016/j.jshs.2014.04.004 · 1.23 Impact Factor
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ABSTRACT: A sequential synthesis of ethylene propylene diene terpolymer-g-poly (styrene-co-acrylonitrile) (EPDM-g-SAN) graft copolymers was carried out via suspension graft copolymerization using benzoyl peroxide (BPO) as an initiator. After the synthesis, the final product was separated by Soxhlet extraction to obtain the styrene-acrylonitrile free copolymer (SANf), non-grafted EPDM and EPDM-g-SAN, which were subsequently characterized by 1H-NMR and FTIR analyses to verify their purity. The dependence of the reaction behaviors on the reaction time was systematically investigated. When the reaction time was varied from 20 min to 100 min, the GPC analysis of the obtained SANf showed a bimodal profile, due to the co-existence of SANL and SANH free copolymers, of low and high molecular weights, which were respectively formed by chain transfer termination and bi-radical termination of the free polymeric radicals. These results revealed that the graft site initiation was dominated by free polymeric radicals attacking the EPDM backbones at the beginning of the grafting process, accompanied by non-grafting copolymerization reactions. On the other hand, the GPC analysis of non-grafted EPDM and EPDM-g-SAN revealed that the reaction mechanism also involved the chain scission of the EPDM molecules which were partly incorporated into the backbone of EPDM-g-SAN and the incorporation of SANf into the grafted chains (g-SAN), resulting in added grafted EPDM and grafting ratio. Furthermore, a novel and effective method was developed to determine the number of g-SAN, and thus the number-average molecular weight of g-SAN was estimated.02/2014; 5(6). DOI:10.1039/C3PY01053H