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
Uwe Beffert, Edwin Weeber, Gerardo Morfini, Jane Ko, Scott T. Brady, Li-Huei Tsai, J. David Sweatt, and Joachim Herz, "Reelin and Cdk5 dependent signals cooperate in regulating neuronal migration and synaptic transmission." J. Neuroscience, 24:1897-1906, 2004
Hans H. Bock and Joachim Herz, "Reelin activates Src family tyrosine kinases in neurons" Current Biology, 13:18-26, 2003
Jochen Brich, Feng-Shiun Shie, Brian W. Howell, Renhua Li, Katalin Tus, Edward K. Wakeland, Lee-Way Jin, Marc Mumby, Gary Churchill, Joachim Herz, and Jonathan A. Cooper, "Genetic modulation of tau phosphorylation in the mouse" J. Neuroscience, 23:187-192, 2003
Philippe Boucher, Pingsheng Liu, Michael Gotthardt, Thomas Hiesberger, Richard G. W. Anderson, and Joachim Herz, "PDGF mediates tyrosine phosphorylation of the cytoplasmic domain of the LDL receptor-relatedprotein (LRP) in caveolae." J. Biol. Chem., 277:15507-13, 2002
Joachim Herz and Hans. H. Bock, "Lipoprotein Receptors in the Nervous System." Ann. Rev. Biochem., 71:405-34, 2002
SIGNIFICANT PUBLICATIONS
Marion Trommsdorff, Michael Gotthardt, Thomas Hiesberger, John Shelton,, "Reeler/Disabled-Like Disruption of Neuronal Migration in Knockout Mice" Cell, 97:689-701, 1999
Thomas Hiesberger, Marion Trommsdorff, Brian W. Howell, Andre Goffinet, Marc, "Direct binding of Reelin to VLDL receptor and ApoE receptor 2 induces" Neuron, 24:481-489, 1999
Michael Gotthardt, Marion Trommsdorff, Matthew F. Nevitt, John Shelton,, "Interactions of the low density lipoprotein (LDL) receptor gene family with" J. Biol. Chem., 275:25616-25624, 2000
Thomas E. Willnow, Zeqi Sheng, Shun Ishibashi, and Joachim Herz, "Inhibition of Hepatic Chylomicron Remnant Uptake by Gene Transfer of A Receptor Antagonist." Science, 264:1471-1474, 1994
Joachim Herz, Ute Hamann, Sissel Rogne, Ola Myklebost, Heinrich Gausepohl, and Keith K. Stanley, "Surface location and high affinity for calcium of a 500 kd liver membrane protein closely related to the LDL receptor suggest a physiological role as lipoprotein receptor." EMBO J., 7:4119-4127, 1988
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