Background and current state of research
Apolipoprotein E (APOE) is a plasma protein and a central mediator of lipid (cholesterol and triglyceride) and lipoprotein metabolism. Its three isoforms E2, E3, and E4 (encoded by the alleles epsilon 2, 3 and 4, respectively) have been observed only in humans. In Western societies, APOE epsilon 4 is associated with increased morbidity and mortality, and represents a significant risk factor for age-related disorders such as atherosclerosis, cardiovascular events or late-onset Alzheimer's disease. The epsilon 4 allele occurs in approximately 14% of the general middle-aged German population. The greater disease risk of epsilon 4 carriers is generally attributed to elevated lipid levels but new evidence indicates that it may also be due to higher oxidative stress and pro-inflammatory states. APOE genotype-dependent effects may be differentially modulated by dietary factors.
This project aims at evaluating interactions on a molecular level between APOE genotype, dietary factors (e.g. caloric restriction) and ageing processes in gene targeted replacement mice applying so-called omics-techniques.
How to get there
APOE targeted replacement mice expressing APOE4, APOE3 or APOE2 will be used as model for phenotypic characterization of APOE genotypes in response to different dietary treatments. Differential gene expression as well as biomarkers will be studied with special regard to traits associated with healthy ageing. Intestinal microbiome analysis may complete phenotypic characterization and help elucidate the interaction of APOE genotypes with dietary factors. Various omics‑techniques will complement molecular biology methods. In addition cell culture experiments using permanent cell lines including hepatocytes and macrophages transfected to express APOE isoforms aim to support the data obtained from targeted replacement mice.
Micro-CT, Foto: Anke Schlösser
Lindahl-Jacobsen R, Tan Q, Mengel-From J, Christensen K, Nebel A, Christiansen L (2013) Effects of the APOE epsilon 2 allele on mortality and cognitive function in the oldest old. J Gerontol A Biol Sci Med Sci in press.
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Flachsbart F, Caliebe A, Kleindorp R, Blanché H, von Eller-Eberstein H, Nikolaus S, Schreiber S, Nebel A (2009) Association of FOXO3A variation with human longevity confirmed in German centenarians. Proceedings of the National Academy of Sciences of the United States of America 106(8):2700-5
Esatbeyoglu T, Huebbe P, Ernst IM, Chin D, Wagner AE, Rimbach G (2012): Curcumin--from molecule to biological function. Angewandte Chemie International Edition English 51(22):5308-32.
Huebbe P, Nebel A, Siegert S, Moehring J, Boesch-Saadatmandi C, Most E, Pallauf J, Egert S, Müller MJ, Schreiber S, Nöthlings U, Rimbach G (2011): APOE ε4 is associated with higher vitamin D levels in targeted replacement mice and humans. FASEB Journal 25(9):3262-3270
Kuhlmann I, Minihane AM, Huebbe P, Nebel A, Rimbach G (2010): Apolipoprotein E genotype and hepatitis C, HIV and herpes simplex disease risk: a literature review. Lipids in Health and Disease 28;9:8