SORCS1 alters amyloid precursor protein processing and variants may increase Alzheimer's disease risk

Authors

  • Christiane Reitz MD, PhD,

    1. The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY
    2. The Gertrude H. Sergievsky Center, Columbia University, New York, NY
    3. Departments of Neurology, Columbia University, New York, NY
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  • Shinya Tokuhiro PhD,

    1. Centre for Research in Neurodegenerative Diseases, University of Toronto
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  • Lorraine N. Clark PhD,

    1. The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY
    2. Departments of Pathology, Columbia University, New York, NY
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  • Christopher Conrad PhD,

    1. The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY
    2. Departments of Pathology, Columbia University, New York, NY
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  • Jean-Paul Vonsattel MD,

    1. The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY
    2. Departments of Pathology, Columbia University, New York, NY
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  • Lili-Naz Hazrati MD, PhD,

    1. Centre for Research in Neurodegenerative Diseases, University of Toronto
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  • András Palotás MD, PhD,

    1. Asklepios-Med, Szeged, Hungary
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  • Raphael Lantigua MD,

    1. The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY
    2. Departments of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY
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  • Martin Medrano MD,

    1. Universidad Tecnológica de Santiago, Santiago, Dominican Republic
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  • Ivonne Z. Jiménez -Velázquez MD,

    1. Department of Internal Medicine, University of Puerto Rico School of Medicine, San Juan, Puerto Rico
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  • Badri Vardarajan MS,

    1. Departments of Medicine (Genetics Program), Boston University Schools of Medicine and Public Health. Boston, MA
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  • Irene Simkin MS,

    1. Departments of Medicine (Genetics Program), Boston University Schools of Medicine and Public Health. Boston, MA
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  • Jonathan L. Haines PhD,

    1. Center for Human Genetics Research and Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN
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  • Margaret A. Pericak -Vance PhD,

    1. Miami Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL
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  • Lindsay A. Farrer PhD,

    1. Departments of Medicine (Genetics Program), Boston University Schools of Medicine and Public Health. Boston, MA
    2. Departments of Neurology, Boston University Schools of Medicine and Public Health. Boston, MA
    3. Departments of Genetics and Genomics
    4. Departments of Epidemiology, Boston University Schools of Medicine and Public Health. Boston, MA
    5. Departments of Biostatistics, Boston University Schools of Medicine and Public Health. Boston, MA
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  • Joseph H. Lee PhD, DrPH,

    1. The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY
    2. The Gertrude H. Sergievsky Center, Columbia University, New York, NY
    3. Department of Epidemiology, School of Public Health, Columbia University, New York, NY
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  • Ekaterina Rogaeva PhD,

    1. Centre for Research in Neurodegenerative Diseases, University of Toronto
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  • Peter St. George- Hyslop MD, FRCP,

    1. Centre for Research in Neurodegenerative Diseases, University of Toronto
    2. Department of Medicine, University Health Network, Toronto, Ontario, Canada
    3. Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
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  • Richard Mayeux MD, MSc

    Corresponding author
    1. The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY
    2. The Gertrude H. Sergievsky Center, Columbia University, New York, NY
    3. Departments of Neurology, Columbia University, New York, NY
    4. Departments of Psychiatry, Columbia University, New York, NY
    5. Departments of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY
    • Gertrude H. Sergievsky Center, 630 West 168th Street, Columbia University, New York, NY 10032
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Abstract

Objective:

Sorting mechanisms that cause the amyloid precursor protein (APP) and the β-secretases and γ-secretases to colocalize in the same compartment play an important role in the regulation of Aβ production in Alzheimer's disease (AD). We and others have reported that genetic variants in the Sortilin-related receptor (SORL1) increased the risk of AD, that SORL1 is involved in trafficking of APP, and that underexpression of SORL1 leads to overproduction of Aβ. Here we explored the role of one of its homologs, the sortilin-related VPS10 domain containing receptor 1 (SORCS1), in AD.

Methods:

We analyzed the genetic associations between AD and 16 SORCS1–single nucleotide polymorphisms (SNPs) in 6 independent data sets (2,809 cases and 3,482 controls). In addition, we compared SorCS1 expression levels of affected and unaffected brain regions in AD and control brains in microarray gene expression and real-time polymerase chain reaction (RT-PCR) sets, explored the effects of significant SORCS1-SNPs on SorCS1 brain expression levels, and explored the effect of suppression and overexpression of the common SorCS1 isoforms on APP processing and Aβ generation.

Results:

Inherited variants in SORCS1 were associated with AD in all datasets (0.001 < p< 0.049). In addition, SorCS1 influenced APP processing. While overexpression of SorCS1 reduced γ-secretase activity and Aβ levels, the suppression of SorCS1 increased γ-secretase processing of APP and the levels of Aβ.

Interpretations:

These data suggest that inherited or acquired changes in SORCS1 expression or function may play a role in the pathogenesis of AD. Ann Neurol 2011;69:47–64.

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