Reelin protects against amyloid β toxicity in vivo

Courtney Lane-Donovan; Gary T Philips; Catherine R Wasser; Murat S Durakoglugil; Irene Masiulis; Ajeet Upadhaya; Theresa Pohlkamp; Cagil Coskun; Tiina Kotti; Laura Steller; Robert E Hammer; Michael Frotscher; Hans H Bock; Joachim Herz

doi:10.1126/scisignal.aaa6674

Reelin protects against amyloid β toxicity in vivo

Sci Signal. 2015 Jul 7;8(384):ra67. doi: 10.1126/scisignal.aaa6674.

Authors

Affiliations

¹ 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.
² Center for Neural Science, New York University, New York, NY 10003, USA.
³ 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.
⁴ Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁵ 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.
⁶ Institute for Structural Neurobiology, Center for Molecular Neurobiology, Hamburg 20251, Germany.
⁷ Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁸ Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich-Heine-University, Düsseldorf 40225, Germany.
⁹ 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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease / genetics
Alzheimer Disease / metabolism
Alzheimer Disease / physiopathology
Amyloid beta-Peptides / metabolism*
Animals
Blotting, Western
Brain / metabolism*
Brain / physiopathology
Cell Adhesion Molecules, Neuronal / genetics
Cell Adhesion Molecules, Neuronal / metabolism*
Extracellular Matrix Proteins / genetics
Extracellular Matrix Proteins / metabolism*
Humans
Immunohistochemistry
LDL-Receptor Related Proteins / metabolism
Long-Term Potentiation / genetics
Long-Term Potentiation / physiology
Maze Learning / physiology
Memory Disorders / genetics
Memory Disorders / physiopathology
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Motor Activity / genetics
Motor Activity / physiology
Nerve Tissue Proteins / genetics
Nerve Tissue Proteins / metabolism*
Receptors, LDL / metabolism
Reelin Protein
Serine Endopeptidases / genetics
Serine Endopeptidases / metabolism*

Substances

Amyloid beta-Peptides
Cell Adhesion Molecules, Neuronal
Extracellular Matrix Proteins
LDL-Receptor Related Proteins
Nerve Tissue Proteins
Receptors, LDL
Reelin Protein
VLDL receptor
low density lipoprotein receptor-related protein 8
RELN protein, human
Reln protein, mouse
Serine Endopeptidases

Abstract

Publication types

MeSH terms

Substances

Grants and funding