title: Reelin protects against amyloid β toxicity in vivo.
abstract: Alzheimer's disease (AD) is a currently incurable neurodegenerative disorder and is the most common form of dementia in people over the age of 65 years. The predominant genetic risk factor for AD is the ε4 allele encoding apolipoprotein E (ApoE4). The secreted glycoprotein Reelin enhances synaptic plasticity by binding to the multifunctional ApoE receptors apolipoprotein E receptor 2 (Apoer2) and very low density lipoprotein receptor (Vldlr). We have previously shown that the presence of ApoE4 renders neurons unresponsive to Reelin by impairing the recycling of the receptors, thereby decreasing its protective effects against amyloid β (Aβ) oligomer-induced synaptic toxicity in vitro. We showed that when Reelin was knocked out in adult mice, these mice behaved normally without overt learning or memory deficits. However, they were strikingly sensitive to amyloid-induced synaptic suppression and had profound memory and learning disabilities with very low amounts of amyloid deposition. Our findings highlight the physiological importance of Reelin in protecting the brain against Aβ-induced synaptic dysfunction and memory impairment.
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. joachim.herz@utsouthwestern.edu courtney.lane@utsouthwestern.edu.
authors.forename: Courtney
authors.initials: C
authors.lastname: Lane-Donovan
authors.affiliation: Center for Neural Science, New York University, New York, NY 10003, USA.
authors.forename: Gary T
authors.initials: GT
authors.lastname: Philips
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Catherine R
authors.initials: CR
authors.lastname: Wasser
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Murat S
authors.initials: MS
authors.lastname: Durakoglugil
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Irene
authors.initials: I
authors.lastname: Masiulis
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Ajeet
authors.initials: A
authors.lastname: Upadhaya
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Center for Neuroscience, Department of Neuroanatomy, Albert-Ludwigs-University, Freiburg 79085, Germany.
authors.forename: Theresa
authors.initials: T
authors.lastname: Pohlkamp
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Cagil
authors.initials: C
authors.lastname: Coskun
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Tiina
authors.initials: T
authors.lastname: Kotti
authors.affiliation: Institute for Structural Neurobiology, Center for Molecular Neurobiology, Hamburg 20251, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Steller
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hammer
authors.affiliation: Institute for Structural Neurobiology, Center for Molecular Neurobiology, Hamburg 20251, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Frotscher
authors.affiliation: Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich-Heine-University, Düsseldorf 40225, Germany.
authors.forename: Hans H
authors.initials: HH
authors.lastname: Bock
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Center for Neuroscience, Department of Neuroanatomy, Albert-Ludwigs-University, Freiburg 79085, Germany. Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. joachim.herz@utsouthwestern.edu courtney.lane@utsouthwestern.edu.
authors.forename: Joachim
authors.initials: J
authors.lastname: Herz
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D026502:LDL-Receptor Related Proteins / Q000378:metabolism; D017774:Long-Term Potentiation / Q000235:genetics / Q000502:physiology; D018782:Maze Learning / Q000502:physiology; D008569:Memory Disorders / Q000235:genetics / Q000503:physiopathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011973:Receptors, LDL / Q000378:metabolism; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D026502:LDL-Receptor Related Proteins; D009419:Nerve Tissue Proteins; D011973:Receptors, LDL; D000091042:Reelin Protein; C036053:VLDL receptor; C098773:low density lipoprotein receptor-related protein 8; C000717127:RELN protein, human; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases