title: Arginine deprivation and immune suppression in a mouse model of Alzheimer's disease.
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.
authors: Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710.
authors: Matthew J
authors: http://orcid.org/0000-0003-4840-2917
authors: MJ
authors: Kan
authors: Department of Neurology, Duke University Medical Center, Durham, North Carolina 27710.
authors: Jennifer E
authors: http://orcid.org/0000-0001-5961-0549
authors: JE
authors: Lee
authors: Department of Neurology, Duke University Medical Center, Durham, North Carolina 27710.
authors: Joan G
authors: JG
authors: Wilson
authors: Department of Neurology, Duke University Medical Center, Durham, North Carolina 27710.
authors: Angela L
authors: AL
authors: Everhart
authors: Department of Neurobiology and Anatomy, West Virginia University School of Medicine, Morgantown, West Virginia 26506.
authors: Candice M
authors: http://orcid.org/0000-0001-5845-0221
authors: CM
authors: Brown
authors: Department of Laboratory Medicine, University of Washington, Seattle, Washington 98195, and.
authors: Andrew N
authors: AN
authors: Hoofnagle
authors: Department of Neurology, Duke University Medical Center, Durham, North Carolina 27710.
authors: Marilyn
authors: M
authors: Jansen
authors: Department of Neurology, Duke University Medical Center, Durham, North Carolina 27710.
authors: Michael P
authors: http://orcid.org/0000-0001-8140-8048
authors: MP
authors: Vitek
authors: Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710, Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710.
authors: Michael D
authors: http://orcid.org/0000-0003-4602-0667
authors: MD
authors: Gunn
authors: Department of Neurology, Duke University Medical Center, Durham, North Carolina 27710, carol.colton@duke.edu.
authors: Carol A
authors: http://orcid.org/0000-0003-3305-370X
authors: CA
authors: Colton
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001120:Arginine / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D000518:Eflornithine / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007155:Immunologic Factors / Q000235:genetics / Q000378:metabolism*; D018782:Maze Learning / Q000187:drug effects; D008570:Memory, Short-Term / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046228:Microarray Analysis; D017628:Microglia / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D065108:Ornithine Decarboxylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D016564:Amyloid beta-Protein Precursor; D015703:Antigens, CD; D007155:Immunologic Factors; D065108:Ornithine Decarboxylase Inhibitors; D001120:Arginine; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D000518:Eflornithine
keywords: Alzheimer's disease; amino acid deprivation; arginase; arginine; immune suppression; microglia