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Articles, Neurobiology of Disease

Arginine Deprivation and Immune Suppression in a Mouse Model of Alzheimer's Disease

Matthew J. Kan, Jennifer E. Lee, Joan G. Wilson, Angela L. Everhart, Candice M. Brown, Andrew N. Hoofnagle, Marilyn Jansen, Michael P. Vitek, Michael D. Gunn and Carol A. Colton
Journal of Neuroscience 15 April 2015, 35 (15) 5969-5982; https://doi.org/10.1523/JNEUROSCI.4668-14.2015
Matthew J. Kan
1Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710,
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Jennifer E. Lee
2Department of Neurology, Duke University Medical Center, Durham, North Carolina 27710,
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Joan G. Wilson
2Department of Neurology, Duke University Medical Center, Durham, North Carolina 27710,
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Angela L. Everhart
2Department of Neurology, Duke University Medical Center, Durham, North Carolina 27710,
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Candice M. Brown
3Department of Neurobiology and Anatomy, West Virginia University School of Medicine, Morgantown, West Virginia 26506,
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Andrew N. Hoofnagle
4Department of Laboratory Medicine, University of Washington, Seattle, Washington 98195, and
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Marilyn Jansen
2Department of Neurology, Duke University Medical Center, Durham, North Carolina 27710,
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Michael P. Vitek
2Department of Neurology, Duke University Medical Center, Durham, North Carolina 27710,
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Michael D. Gunn
1Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710,
5Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710
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Carol A. Colton
2Department of Neurology, Duke University Medical Center, Durham, North Carolina 27710,
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Abstract

The pathogenesis of Alzheimer's disease (AD) is a critical unsolved question; and although recent studies have demonstrated a strong association between altered brain immune responses and disease progression, the mechanistic cause of neuronal dysfunction and death is unknown. We have previously described the unique CVN-AD mouse model of AD, in which immune-mediated nitric oxide is lowered to mimic human levels, resulting in a mouse model that demonstrates the cardinal features of AD, including amyloid deposition, hyperphosphorylated and aggregated tau, behavioral changes, and age-dependent hippocampal neuronal loss. Using this mouse model, we studied longitudinal changes in brain immunity in relation to neuronal loss and, contrary to the predominant view that AD pathology is driven by proinflammatory factors, we find that the pathology in CVN-AD mice is driven by local immune suppression. Areas of hippocampal neuronal death are associated with the presence of immunosuppressive CD11c+ microglia and extracellular arginase, resulting in arginine catabolism and reduced levels of total brain arginine. Pharmacologic disruption of the arginine utilization pathway by an inhibitor of arginase and ornithine decarboxylase protected the mice from AD-like pathology and significantly decreased CD11c expression. Our findings strongly implicate local immune-mediated amino acid catabolism as a novel and potentially critical mechanism mediating the age-dependent and regional loss of neurons in humans with AD.

  • Alzheimer's disease
  • amino acid deprivation
  • arginase
  • arginine
  • immune suppression
  • microglia
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The Journal of Neuroscience: 35 (15)
Journal of Neuroscience
Vol. 35, Issue 15
15 Apr 2015
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Arginine Deprivation and Immune Suppression in a Mouse Model of Alzheimer's Disease
Matthew J. Kan, Jennifer E. Lee, Joan G. Wilson, Angela L. Everhart, Candice M. Brown, Andrew N. Hoofnagle, Marilyn Jansen, Michael P. Vitek, Michael D. Gunn, Carol A. Colton
Journal of Neuroscience 15 April 2015, 35 (15) 5969-5982; DOI: 10.1523/JNEUROSCI.4668-14.2015

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Arginine Deprivation and Immune Suppression in a Mouse Model of Alzheimer's Disease
Matthew J. Kan, Jennifer E. Lee, Joan G. Wilson, Angela L. Everhart, Candice M. Brown, Andrew N. Hoofnagle, Marilyn Jansen, Michael P. Vitek, Michael D. Gunn, Carol A. Colton
Journal of Neuroscience 15 April 2015, 35 (15) 5969-5982; DOI: 10.1523/JNEUROSCI.4668-14.2015
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Keywords

  • Alzheimer's disease
  • amino acid deprivation
  • arginase
  • arginine
  • immune suppression
  • microglia

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