Alzheimer’s disease and atherosclerosis are progressive degenerative syndromes that together afflict more than 50% of the population in Western societies. Their prevalence and socioeconomic impact is steadily increasing along with average life expectancy.
Our work has identified several fundamental molecular mechanisms that are common to both of these superficially unrelated diseases. They are mediated by a class of ancient and evolutionarily highly conserved cell surface receptors known as the LDL receptor gene family. The core of this family consists of seven structurally closely related multifunctional receptors that share partly overlapping roles in such diverse biological processes as receptor-mediated endocytosis, regulation of extracellular protease activity, hormone transport, and intercellular signaling. The range of physiological functions in which the receptors are involved includes lipid metabolism, neuronal migration during brain development, neurotransmission, axonal transport, vitamin metabolism, and the control of cellular proliferation. All members of the family are also receptors for Apolipoprotein E (ApoE), a major risk factor gene for late-onset Alzheimer?s disease. One of our goals is to understand, how the interaction of ApoE and other physiological ligands with its receptors affects the cell biology of the neuron.
In our group we use refined conventional and conditional gene targeting and transgenic approaches in mice to investigate the molecular basis on which LDL receptor family members control pivotal mechanisms of cellular communication during embryonic development and in the adult organism. We are using numerous strains of mice with compound mutations in multiple genes to investigate i) the role of the ApoE receptor-2 and the VLDL receptor and their ligand Reelin in neuronal migration, axonal transport, neurotransmission and neurodegeneration, and ii) the role of the LDL receptor-related protein (LRP) in the regulation of vascular remodeling and integrity.
For an up-to-date list of publications please visit:
http://publications.herzlab.org
RESEARCH INTERESTS
Physiological functions of the LDL receptor gene family
Lipid Metabolism and Atherosclerosis
Brain Development and Alzheimer’s Disease
RECENT PUBLICATIONS
Matt Larouche, Uwe Beffert, Joachim Herz, and Richard Hawkes, "The Reelin Receptors Apoer2 and Vldlr Coordinate the Patterning of Purkinje Cell Topography in the Developing Mouse Cerebellum" PLoS ONE, 3:e1653, 2008
Alin L. Akopians, Alex H. Babayan, Uwe Beffert, Joachim Herz, Allan I. Basbaum and Patricia E. Phelps, "Contribution of the Reelin signaling pathways to nociceptive processing" Eur. J. Neuroscience, 27:523-537, 2008
Qiang Liu, Celina V. Zerbinatti, Juan Zhang, Hyang-Sook Hoe, Baiping Wang, Sarah L. Cole, Joachim Herz, Louis Muglia, and Guojun Bu, "Amyloid Precursor Protein Regulates Brain Apolipoprotein E and Cholesterol Metabolism through Lipoprotein Receptor LRP1" Neuron, 56:66-78, 2007
Susanna M. Hofmann, Li Zhou, Diego Perez-Tilve, Todd Greer, Erin Grant, Lauren Wancata, Andrew Thomas, Paul T. Pfluger, Joshua E. Basford, Dean Gilham, Joachim Herz, Matthias H. Tschop, and David Y. Hui, "Adipocyte LDL receptor related protein-1 expression modulates postprandial lipid transport, glucose homeostasis, and adiposity" J. Clin. Invest., 117:3271-3282, 2007
Philippe Boucher, Wei-Ping Li, Rachel L. Matz, Yoshiharu Takayama, Johan Auwerx, Richard G.W. Anderson, Joachim Herz, "LRP1 Functions as an Atheroprotective Integrator of TGFβ and PDFG Signals in the Vascular Wall: Implications for Marfan Syndrome" PLoS ONE, 2:e448, 1-2, 2007
SIGNIFICANT PUBLICATIONS
Thomas Hiesberger, Marion Trommsdorff, Brian W. Howell, Andre Goffinet, Marc, "Direct binding of Reelin to VLDL receptor and ApoE receptor 2 induces tyrosine phosphorylation of the adaptor protein Disabled-1 and modulates the tau phosphorylation" Neuron, 24:481-489, 1999
Edwin J. Weeber, Uwe Beffert, Chris Jones, Jill M. Christian, Eckart Forster, J. David Sweatt, and Joachim Herz, "Reelin and ApoE receptors cooperate to enhance hippocampal synaptic plasticity and learning." J Biol Chem., 277:39944-39952, 2002
Uwe Beffert, Edwin J. Weeber, Andre Durudas, Shenfeng Qiu, Irene Masiulis, J. David Sweatt, Wei-Ping Li, Giselind Adelmann, Michael Frotscher, Robert E. Hammer, and Joachim Herz, "Modulation of Synaptic Plasticity and Memory by Reelin Involves Differential Splicing of the Lipoprotein Receptor Apoer2." Neuron, 47:567-579, 2005
Ying Chen, Uwe Beffert, Mert Ertunc, Tie-Shan Tang, Ege T. Kavalali, Ilya Bezprozvanny, Joachim Herz, "Reelin Modulates NMDA Receptor Activity in Cortical Neurons." J. Neuroscience, 25:8209-8216, 2005
Uwe Beffert, Farnas Nematollah-Farsian, Irene Masiulis, Robert Hammer, Sung Ok Yoon, Klaus M. Giehl, and Joachim Herz, "ApoE receptor 2 controls neuronal survival in the adult brain" Current Biology, 16:2446-2452, 2006
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