Members of the low-density-lipoprotein (LDL) receptor gene family have recently been found to participate in signal transduction pathways during the development of the brain. Reelin, a large secreted protein that bears no resemblance to lipoproteins and is not involved in lipid transport, binds to the extracellular domains of two members of this gene family, termed VLDL receptor (VLDLR) and ApoE receptor 2 (ApoER2). Binding of this ligand activates a cytoplasmic signaling cascade that apparently involves tyrosine kinases as well as the serine/threonine kinases Cdk5 and GSK-3beta. Disruption of this pathway results in abnormal phosphorylation of the microtubule-associated protein tau and therefore is likely to impair axonal transport processes, which are dependent on the normal function of microtubules. ApoER2 and VLDLR both are expressed abundantly on the surface of embryonic neurons as well as on neurons in the mature brain, where they can also function as receptors for Apolipoprotein E (ApoE). ApoE exists in three major isoforms. One of these isoforms, ApoE4 is genetically associated with late-onset Alzheimer disease. The biochemical basis by which ApoE4 predisposes its carriers to late-onset Alzheimer disease is poorly understood. We hypothesize that ApoE4 acts as a competitor for signaling molecules such as Reelin and reduces their binding to the receptors on the neuronal surface, thereby impairing physiological signaling pathways that regulate neuronal transport and synaptic protein transport. This model would provide a mechanistic basis on which the loss of synapses, which correlates with dementia and precedes the formation of plaques and neurofibrillary tangles, could be explained. The goal of the current proposal is to elucidate the cytoplasmic signaling pathways that are activated by the binding of Reelin to its receptors on the neuronal cell surface and to study the effect of Reelin on axonal transport, the activity of molecular motors such as dynein and kinesin, and the transport of synaptic proteins to their target sites.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS043408-05
Application #
7026938
Study Section
Special Emphasis Panel (ZRG1-MDCN-1 (01))
Program Officer
Sutherland, Margaret L
Project Start
2002-03-15
Project End
2009-02-28
Budget Start
2006-03-01
Budget End
2009-02-28
Support Year
5
Fiscal Year
2006
Total Cost
$361,794
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Genetics
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
van de Sluis, Bart; Wijers, Melinde; Herz, Joachim (2017) News on the molecular regulation and function of hepatic low-density lipoprotein receptor and LDLR-related protein 1. Curr Opin Lipidol 28:241-247
Ding, Yinyuan; Xian, Xunde; Holland, William L et al. (2016) Low-Density Lipoprotein Receptor-Related Protein-1 Protects Against Hepatic Insulin Resistance and Hepatic Steatosis. EBioMedicine 7:135-45
Lane-Donovan, Courtney; Philips, Gary T; Herz, Joachim (2014) More than cholesterol transporters: lipoprotein receptors in CNS function and neurodegeneration. Neuron 83:771-87
Sekine, Katsutoshi; Kawauchi, Takeshi; Kubo, Ken-Ichiro et al. (2012) Reelin controls neuronal positioning by promoting cell-matrix adhesion via inside-out activation of integrin ?5?1. Neuron 76:353-69
Boucher, Philippe; Herz, Joachim (2011) Signaling through LRP1: Protection from atherosclerosis and beyond. Biochem Pharmacol 81:1-5
Forster, Eckart; Bock, Hans H; Herz, Joachim et al. (2010) Emerging topics in Reelin function. Eur J Neurosci 31:1511-8
Brunne, Bianka; Zhao, Shanting; Derouiche, Amin et al. (2010) Origin, maturation, and astroglial transformation of secondary radial glial cells in the developing dentate gyrus. Glia 58:1553-69
Pigino, G; Morfini, G; Atagi, Y et al. (2009) Disruption of fast axonal transport is a pathogenic mechanism for intraneuronal amyloid beta. Proc Natl Acad Sci U S A 106:5907-12
Szodorai, Anita; Kuan, Yung-Hui; Hunzelmann, Silke et al. (2009) APP anterograde transport requires Rab3A GTPase activity for assembly of the transport vesicle. J Neurosci 29:14534-44
Zhou, Li; Takayama, Yoshiharu; Boucher, Philippe et al. (2009) LRP1 regulates architecture of the vascular wall by controlling PDGFRbeta-dependent phosphatidylinositol 3-kinase activation. PLoS One 4:e6922

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