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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; DOI: 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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  • Figure 1.
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    Figure 1.

    Expression of immune-related genes from whole-brain lysates. Average values and SEM for the relative change in mRNA levels are shown for immune-related genes from whole-brain lysate samples from CVN-AD, mNos2−/−, WT (C57BL/6), and APPSwDI mice. A–D, Genes that were upregulated in CVN-AD mice before 36 weeks of age. E–I, Genes that were upregulated in CVN-AD mice at or after 36 weeks of age. J–L, Gene expression of chemokine receptors. mRNA expression was measured using quantitative RT-PCR and represent the 2(−delta delta C(T)) compared with WT mice. Samples were analyzed by two-way ANOVA and post hoc multiple comparison test with Bonferonni's correction. *Comparisons between CVN-AD or APPSwDI and WT. #Comparisons between CVN-AD and APPSwDI mice. *p < 0.05. **p < 0.01. ***p < 0.001. ****p < 0.0001. #p < 0.05. ##p < 0.01. ###p < 0.001. ####p < 0.0001. n > 5 mice per group.

  • Figure 2.
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    Figure 2.

    CVN-AD amyloid deposition is associated with cells expressing characteristic markers of microglia. Representative sagittal sections from a CVN-AD mouse at 6, 12, 24, and 52 weeks of age immunostained for Aβ (A–D), CD45 (E–H), Iba-1 (I–L), and CD11c (M–P). For each age, panels represent sister sections from the same mouse. For example, A, E, I, and M are sections from the same 6-week-old mouse. Scale bar, 500 μm. Q, Representative micrographs of CD11c and Iba-1 costaining in the subiculum of the hippocampus from a 24-week-old CVN-AD mouse. Scale bar, 25 μm. R, Increased CD11c immunostaining is associated with increased total brain gene expression of CD11c (Itgax). Gene expression levels (mean ± SEM) were measured using quantitative RT-PCR and represent the 2(−delta delta C(T)) compared with WT mice. Samples were analyzed by two-way ANOVA and post hoc multiple comparison test with Bonferonni's correction. *Comparisons between CVN-AD or APPSwDI and WT. #Comparisons between CVN-AD and APPSwDI mice. *p < 0.05. **p < 0.01. ***p < 0.001. ****p < 0.0001. #p < 0.05. ##p < 0.01. ###p < 0.001. ####p < 0.0001. n > 5 mice per group.

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    Figure 3.

    CD11c+ cells from CVN-AD brains have a microglial phenotype. A, Representative flow cytometry plots from aged 48-week-old mNos2−/− and CVN-AD brains after gating on CD45+ cells. B, Quantification of total CD45+ cells and individual cell types distinguished by FACS in 48-week-old mNos2−/− and CVN-AD brains, including T lymphocytes (T), B lymphocytes (B), neutrophils (PMN), monocytes/macrophages/DCs (Mac/DC), and microglia (MG) from aged 48-week-old mNos2−/− and CVN-AD brains. *p < 0.05; ****p < 0.0001. C, Representative flow plots of CD45 and CD11c expression from aged 48-week-old mNos2−/− and CVN-AD brains after gating on all CD11b+ cells. D, Representative histogram of CD11c expression on mNos2−/− (closed gray) and CVN-AD (open black) CD11b+ CD45low cells, as well as quantitative summaries of the percentages and geometric mean fluorescence intensities of CD11c from mNos2−/− and CVN-AD CD11b+ CD45low microglia. *p < 0.01. n = 4 mice per group.

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    Figure 4.

    CVN-AD pathology is associated with arginase-1. A, Representative sagittal sections from CVN-AD mice at 6, 12, 24, and 52 weeks of age stained for arginase-1 in sister sections from the same mice as in Figure 1. Scale bar, 500 μm. B, Magnified view of arginase immunoreactivity in the subiculum. Representative sagittal sections from 24-week-old mNos2−/− and CVN-AD stained for arginase-1. Scale bars: top, 500 μm; bottom, 50 μm. C, Sister coronal sections from the same 52-week-old CVN-AD brain stained for Aβ, CD11c, Iba-1, and arginase-1 to show regional associations.

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    Figure 5.

    CVN-AD brains have decreased total l-arginine bioavailability and increased expression of arginine transporters. A, Global arginine bioavailability (arginine/(ornithine + citrulline)) for CVN-AD, mNos2−/−, WT, and APPSwDI mice. Average values (± SEM) per genotype were calculated for individual mice (n = 3–12 mice per group). Amino acid levels were measured using HILIC LC-MS/MS. **p < 0.01 (one-way ANOVA). B–E, Relative gene expression (mean ± SEM) was measured in total brain homogenates from CVN-AD, mNos2−/−, WT, and APPSwDI mice for the neutral arginine transporters Slc7a5 (LAT1) and Slc7a8 (LAT2) (B, C) and for the cationic amino acid transporters Slc7a1 (CAT1) and Slc7a2 (CAT2) (D, E). Samples were analyzed by two-way ANOVA and post hoc multiple comparison test with Bonferonni's correction. *Comparisons between CVN-AD or APPSwDI and WT. #Comparisons between CVN-AD and APPSwDI mice. *p < 0.05. **p < 0.01. ***p < 0.001. ****p < 0.0001. #p < 0.05. ##p < 0.01. ###p < 0.001. ####p < 0.0001. n = 4–8 mice per group.

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    Figure 6.

    CVN-AD memory deficits and pathology are reversed by an inhibitor of arginine utilization. A, RAWM assessment of spatial memory acquisition and recall in CVN-AD mice treated with putrescine (put.) alone or putrescine and DFMO (10 mg/kg) by oral gavage for 3 d/week for 14 weeks. All mice were naive to the behavioral procedure and tested on the final 2 d of treatment. Day 1 depicts 5 trial groups for the acquisition phase (learning), and day 2 depicts successive trials for memory recall. Data represent the average number of errors (± SEM) made finding the escape platform for each group of trials. Open circles represent CVN-AD mice treated with putrescine and vehicle. Closed circles represent CVN-AD mice treated with DFMO and putrescine. Data were analyzed by two-way ANOVA and post hoc multiple comparison test with Bonferonni's correction. ***p < 0.001. n = 7 or 8 mice per group. B, Soluble and insoluble Aβ40 and Aβ42 peptides in total brain homogenates from CVN-AD mice treated with vehicle containing putrescine only or putrescine plus DFMO as measured by ELISA. Data represent average levels (± SEM) of Aβ40 or Aβ42 peptides. ***p < 0.001 for DFMO-treated compared with putrescine/vehicle-treated using an unpaired Student's t test. n = 7 or 8 mice/group. C, DFMO treatment alters mRNA levels of immune genes. Average mRNA expression levels (± SEM) for Itgax, Pdcd1 (programmed death receptor 1), Arg1, and Ssat were measured in total brain lysates from CVN-AD mice treated with putrescine in vehicle or putrescine and DFMO. Gene expression levels were measured using quantitative RT-PCR and represent the 2(−delta delta C(T)) with untreated mice as the comparator. Significance between untreated and treated was determined using the unpaired Student's t test. *p < 0.05. **p < 0.01. n = 7 or 8 mice per group. D, Representative sagittal sections from CVN-AD mice treated with either putrescine alone or putrescine and DFMO stained for Aβ or CD11c. For each treatment group, panels represent sister sections from the same mouse. Scale bar, 500 μm.

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    Figure 7.

    Simplified schematic of arginine catabolism and the actions of DFMO to block arginine utilization. NOHA, N-hydroxyarginine. Gray text indicates a reduction of this protein/product in CVN-AD mice.

Tables

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    Table 1.

    Gene expression in CVN-AD CD11c+ microglia compared with CVN-AD CD11c− microglia, C57BL/6 microglia, and mNos2−/− microgliaa

    GeneNameFold changep valueReported actionsReferences
    MamdcMAM domain containing protein 25159.7 × 10−7Glycosaminoglycan binding, linked to negative regulation of synapsesPettem et al., 2013
    Spp1Secreted phosphoprotein 1; osteopontin5155.9 × 10−6Increased in CSF of AD patients; enhances immunosuppressionComi et al., 2010; Sangaletti et al., 2014
    GpnmbGlycoprotein-transmembrane nmb; osteoactivin, Fe65-like14421.5 × 10−6Tissue repair, M2 state; phagocytic vesicle processingDuffield, 2010
    Wfdc17Whey acidic protein four disulfide core domain 17; AMWAP1364.1 × 10−5Overexpression increases Arg-1, reduces IL-6, IL-1βKarlstetter et al., 2010
    ItgaxIntegrin alpha X (complement component 3 receptor 4 subunit), CD11c1245.8 × 10−6Leukocyte-specific integrin; associated with dendritic cells; phagocytosis of complement-coated particles; found on microglia in ADAkiyama and McGeer, 1990; Tooyama et al., 1990; Becher and Antel, 1996; Butovsky et al., 2007
    Gp49aGlycoprotein 49a; Lirb41072.8 × 10−4Member of inhibitory Ig superfamily; increased IL-4; suppresses LPS; inhibits Fc-gamma-mediated phagocytosisArm et al., 1997; McCormick et al., 1999
    Gng12Guanine nucleotide binding protein 12641.7 × 10−4Inhibits LPS-mediated pro-inflammationLarson et al., 2010
    Pdcd1Programmed cell death 1; PD-L1, CD279514.1 × 10−6Immunoglobin superfamily; shifts microglia to M2 phenotype; regulates Arg-1 activityYao et al., 2014
    Apbb2Amyloid precursor protein binding protein 225.82.4 × 10−4Adaptor protein binds to cytoplasmic domain of APP; polymorphisms associated with dementia in aged population; involved in ECM synthesis by MacsWright et al., 2005; Grupe et al., 2006; Golanska et al., 2013
    TIMP2Tissue inhibitor of metalloprotease-220.73.2 × 10−4Blocks metalloprotease activity; associated with M2 phenotypeRidnour et al., 2007; Wilcock et al., 2011a
    Igf1Insulin-like growth factor 1; 2; somatomedin c27.42.0 × 10−5Found in human microglia, protects from IL-1- and IFN-γ-mediated damage; promotes Aβ clearanceTrueba-Sáiz et al., 2013
    Igf28.02.1 × 10−3
    ApoeApolipoprotein E20.13.6 × 10−4Strongest single gene risk factor for AD, suppresses proinflammatory cytokinesSaunders et al., 1996
    CD200rCell surface glycoprotein CD200 receptor 2, OX2R13.83.3 × 10−3Inhibitory immune receptor found on microglia, marker for M2 activation in human MG, less so in miceDenieffe et al., 2013; Walker and Lue, 2013
    Klf6Kruppel-like factor 60.124.9 × 10−6Suppression is linked to M2 phenotypeDate et al., 2014
    Apobec3Apolipoprotein B mRNA editing enzyme, catalytic polypeptide 30.184.1 × 10−4Promotes antiviral immunity through production of neutralizing antibodySantiago et al., 2008
    Ifngr1Interferon-γ receptor 1; CD1190.199.1 × 10−6Encodes ligand binding domain for IFN-γ; downregulated by TLR2; IFN-βCurry et al., 2004; Kearney et al., 2013
    SiglechSiglec-H0.422.6 × 10−4DAP12 signaling molecule, microglial “sensome,” decreased with agingHickman et al., 2013
    • ↵aSelect genes that were significantly upregulated or downregulated in CVN-AD CD11c+ microglia compared with CVN-AD CD11c− microglia, C57BL/6 microglia, and mNos2−/− microglia, including fold change in expression, p value, and reported actions with references.

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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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