Lipoprotein receptors have essential functions in the control of plasma lipid levels and are critically important for protection of the arteries from atherosclerosis and coronary artery disease. The low-density lipoprotein (LDL) receptor gene family represents one class of such receptors that bind the lipid transport protein Apolipoprotein E. Three isoforms of ApoE exist in the human population, E2, E3 and E4. ApoE4 is genetically associated with increased risk for two major, but clinically very different diseases that are prevalent in our Western populations: Atherosclerosis and Alzheimer's disease (AD). The molecular mechanisms through which ApoE4 genotype predisposes to higher circulating LDL levels on one hand, and to increased neuronal vulnerability and accelerated degeneration in AD on the other, are poorly understood. Understanding the role of ApoE in these disease processes, however, is of rapidly increasing socioeconomic importance in our Western societies, where the continuing increase in average life-expectancy has led to an epidemic of age- related vascular and neurological debilities. The purpose of this proposal is to investigate the molecular and cellular mechanisms by which ApoE promotes disease onset and progression, and to determine the role of the ApoE receptors Vldlr and Apoer2 in the process. Both proteins are not only receptors for ApoE, but also for Reelin, an indispensable neurodevelopmental signaling protein that further controls synaptic plasticity by activating Vldlr and Apoer2 in the adult brain. ApoE is produced abundantly by glial cells in the CNS, where we hypothesize that it interferes with Apoer2 and Vldlr functions, thereby contributing to the pathogenesis of AD. Intriguingly, ApoE, Reelin, Apoer2 and Vldlr also cross paths in the periphery at the vascular wall. Reelin is secreted by the liver and circulates in blood in concentrations similar to those present in the CNS. Its role in the blood is unknown, but the Reelin receptors Apoer2 and Vldlr have protective roles in the maintenance of the vascular wall. This proposal explores the function of Reelin at the vessel wall and investigates molecular mechanisms through which ApoE interferes in an isoform-specific manner with ApoE receptor functions and Reelin signaling in the vascular wall and in neurons. The proposed work involves the analysis of the vascular physiology of conditional Reelin knockout mice, the effect of naturally occurring and mutant ApoE isoforms on subcellular ApoE receptor trafficking and recycling, and detailed quantitative measurements of Reelin signaling functions in cells. The results from these studies will contribute a conceptually novel mechanistic basis to our understanding of the pathogenesis of atherosclerosis, as well as ApoE-mediated neurodegenerative processes.
Atherosclerosis and neurodegeneration are two major age-related diseases in our Western societies. Apolipoprotein E, a lipid and cholesterol transport protein, is a major genetic modifier for both syndromes. This application investigates the role of ApoE receptors in cellular signaling pathways that are common to both disease processes and explores the molecular mechanisms by which certain ApoE genotypes predispose to vascular and neuronal pathogenesis.
|Ding, Yinyuan; Huang, Linzhang; Xian, Xunde et al. (2016) Loss of Reelin protects against atherosclerosis by reducing leukocyte-endothelial cell adhesion and lesion macrophage accumulation. Sci Signal 9:ra29|
|Ulrich, Victoria; Gelber, Shari E; Vukelic, Milena et al. (2016) ApoE Receptor 2 Mediation of Trophoblast Dysfunction and Pregnancy Complications Induced by Antiphospholipid Antibodies in Mice. Arthritis Rheumatol 68:730-9|
|El Asmar, Zeina; Terrand, JÃ©rome; Jenty, Marion et al. (2016) Convergent Signaling Pathways Controlled by LRP1 (Receptor-related Protein 1) Cytoplasmic and Extracellular Domains Limit Cellular Cholesterol Accumulation. J Biol Chem 291:5116-27|
|Lane-Donovan, Courtney; Herz, Joachim (2016) High-Fat Diet Changes Hippocampal Apolipoprotein E (ApoE) in a Genotype- and Carbohydrate-Dependent Manner in Mice. PLoS One 11:e0148099|
|Lane-Donovan, Courtney; Desai, Charisma; Pohlkamp, Theresa et al. (2016) Physiologic Reelin does not play a strong role in protection against acute stroke. J Cereb Blood Flow Metab 36:1295-303|
|Beer, Arno G; Zenzmaier, Christoph; Schreinlechner, Michael et al. (2016) Expression of a recombinant full-length LRP1B receptor in human non-small cell lung cancer cells confirms the postulated growth-suppressing function of this large LDL receptor family member. Oncotarget :|
|Strecker, Paul; Ludewig, Susann; Rust, Marco et al. (2016) FE65 and FE65L1 share common synaptic functions and genetically interact with the APP family in neuromuscular junction formation. Sci Rep 6:25652|
|Eldridge, Suzanne; Nalesso, Giovanna; Ismail, Habib et al. (2016) Agrin mediates chondrocyte homeostasis and requires both LRP4 and Î±-dystroglycan to enhance cartilage formation in vitro and in vivo. Ann Rheum Dis 75:1228-35|
|Lane-Donovan, Courtney; Wong, Wen Mai; Durakoglugil, Murat S et al. (2016) Genetic Restoration of Plasma ApoE Improves Cognition and Partially Restores Synaptic Defects in ApoE-Deficient Mice. J Neurosci 36:10141-50|
|Wasser, Catherine R; Herz, Joachim (2016) Splicing therapeutics for Alzheimer's disease. EMBO Mol Med 8:308-10|
Showing the most recent 10 out of 75 publications