Alzheimer Disease: Herz J

Herz J. · Department of Molecular Genetics, UT Southwestern, Dallas, Texas 75390-9046, USA. · Curr Opin Lipidol. · Pubmed #19433918 No free full text.

Abstract: PURPOSE OF REVIEW: Over the past few years, apolipoprotein E (ApoE) receptors, also known as LDL receptor-related proteins, have distinguished themselves as functionally diverse signaling receptors with pivotal roles not only in the vascular system but also in the nervous system and during development. RECENT FINDINGS: The expanding roles of ApoE receptors for cellular signal transduction at the same time transcend and integrate their lipid transport roles into a larger biological and clinical context. ApoE receptors are essential for the development of the nervous system, the regulation of synaptic plasticity, neuroprotection and the innervation of the muscle. They also regulate the metabolism of the amyloid precursor protein on multiple levels, implicating them in the pathogenesis of Alzheimer's disease. SUMMARY: ApoE, a common ligand for all members of the evolutionarily ancient LDL receptor gene family, is the major genetic modifier of the age of onset of Alzheimer's disease. The underlying molecular mechanisms remain shrouded in mystery, but the numerous critical functions of ApoE receptors within and outside the nervous system that have recently emerged make it likely that these multifunctional signal modulators participate in Alzheimer's disease pathogenesis. This review attempts to summarize the most recent and relevant findings in this area.

Herz J. · Department of Molecular Genetics, UT Southwestern, Dallas, TX 75390, USA. · Neuron. · Pubmed #17296548 No free full text.

This publication has no abstract.

Herz J, Strickland DK. · Department of Molecular Genetics, Dallas, Texas, USA. · J Clin Invest. · Pubmed #11560943 links to  free full text

This publication has no abstract.

Herz J. · Department of Molecular Genetics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA. · Neuron. · Pubmed #11301018 No free full text.

This publication has no abstract.

Herz J, Beffert U. · Department of Molecular Genetics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9046, USA. · Nat Rev Neurosci. · Pubmed #11252768 No free full text.

Abstract: Alzheimer's disease is a debilitating neurodegenerative disorder that afflicts an increasing part of our ageing population. An isoform of apolipoprotein E, a protein that mediates the transport of lipids and cholesterol in the circulatory system, predisposes carriers of this allele to the common late-onset form of the disease. How this protein is related to a neurodegenerative disorder is an enigma. Mounting evidence indicates that apolipoprotein E receptors, which are abundantly expressed in most neurons in the central nervous system, also fulfill critical functions during brain development and may profoundly influence the pathogenesis of Alzheimer's disease.

Herz J. · Department of Molecular Genetics, UT Southwestern, 5323 Harry Hines Boulevard, Dallas, TX 75390-9046, USA. · Trends Neurosci. · Pubmed #11249989 No free full text.

Abstract: Lipoprotein receptors were originally considered simply as cellular transporters for cholesterol and other lipids. This view is rapidly changing. Signaling functions have recently been recognized in several members of the low-density lipoprotein receptor gene family. These Apolipoprotein E receptors are highly expressed in the developing and in the mature nervous system, in which they regulate crucial developmental processes and might also participate in synaptic neurotransmission.

Herz J, Gotthardt M, Willnow TE. · Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas 75235-9046, USA. · Curr Opin Lipidol. · Pubmed #10787178 No free full text.

Abstract: Lipoprotein receptors are commonly thought merely to mediate the internalization of lipoprotein particles or the exchange of lipids at the cell surface. Recent findings have now implicated these multifunctional receptors in cellular signalling mechanisms that extend beyond simple ligand endocytosis. By mediating the cellular uptake of lipophilic vitamins and hormones, megalin, a member of the LDL receptor gene family, regulates critical hormonal and metabolic processes. Other members of the LDL receptor family interact with cytoplasmic adaptor and scaffold proteins, which allows them to transmit signals directly across the plasma membrane of the target cell. This sheds a new light on the emerging roles of lipoprotein receptors in pathologic disease processes such as Alzheimer's disease.

Brich J, Shie FS, Howell BW, Li R, Tus K, Wakeland EK, Jin LW, Mumby M, Churchill G, Herz J, Cooper JA. · Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. · J Neurosci. · Pubmed #12514215 links to  free full text

Abstract: The axonal microtubule stabilizing protein tau is hyperphosphorylated in several neurodegenerative conditions, including Alzheimer's disease, yet the genes that regulate tau phosphorylation are largely unknown. Disabled-1 (Dab1) is a cytoplasmic adapter protein that interacts with apolipoprotein E (ApoE) receptors and controls neuronal positioning during embryonic brain development. We have investigated the role of Dab1 in tau phosphorylation. We found that wild-type Dab1, but not a mutant lacking tyrosine phosphorylation sites, protects mice from the hyperphosphorylation of tau. However, the absence of Dab1 is not sufficient to cause tau hyperphosphorylation, because hyperphosphorylation is manifested only when Dab1 is mutated in specific mouse strain backgrounds. Tau hyperphosphorylation correlates with early death in susceptible mouse strains, and it occurs in the neurons of the hippocampus and dentate gyrus. By quantitative trait locus (QTL) analysis of Dab1-deficient mice on a hybrid strain background, we uncovered one significant and three suggestive chromosomal loci that modulate tau phosphorylation. Two of these QTL regions contain genes that are defective in early onset Alzheimer's disease. Our findings suggest that Dab1 gene disruption sensitizes mice to tau hyperphosphorylation contingent on specific haplotypes that are linked to Alzheimer's disease loci. Dab1 mutant mice provide an animal model for studying the relationships between ApoE receptors, tau hyperphosphorylation, and Alzheimer's disease.

Weeber EJ, Beffert U, Jones C, Christian JM, Forster E, Sweatt JD, Herz J. · Division of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, USA. · J Biol Chem. · Pubmed #12167620 links to  free full text

Abstract: Two apolipoprotein E (apoE) receptors, the very low density lipoprotein (VLDL) receptor and apoE receptor 2 (apoER2), are also receptors for Reelin, a signaling protein that regulates neuronal migration during brain development. In the adult brain, Reelin is expressed by GABA-ergic interneurons, suggesting a potential function as a modulator of neurotransmission. ApoE receptors have been indirectly implicated in memory and neurodegenerative disorders because their ligand, apoE, is genetically associated with Alzheimer disease. We have used knockout mice to investigate the role of Reelin and its receptors in cognition and synaptic plasticity. Mice lacking either the VLDL receptor or the apoER2 show contextual fear conditioning deficits. VLDL receptor-deficient mice also have a moderate defect in long term potentiation (LTP), and apoER2 knockouts have a pronounced one. The perfusion of mouse hippocampal slices with Reelin has no effect on baseline synaptic transmission but significantly enhances LTP in area CA1. This Reelin-dependent augmentation of LTP is abolished in VLDL receptor and apoER2 knockout mice. Our results reveal a role for Reelin in controlling synaptic plasticity in the adult brain and suggest that both of its receptors are necessary for Reelin-dependent enhancement of synaptic transmission in the hippocampus. Thus, the impairment of apoE receptor-dependent neuromodulation may contribute to cognitive impairment and synaptic loss in Alzheimer disease.