Muramyl dipeptide-mediated immunomodulation on monocyte subsets exerts therapeutic effects in a mouse model of Alzheimer's disease

被引:19
作者
Fani Maleki, Adham [1 ,2 ]
Cisbani, Giulia [1 ,2 ]
Plante, Marie-Michele [1 ,2 ]
Prefontaine, Paul [1 ,2 ]
Laflamme, Nataly [1 ,2 ]
Gosselin, Jean [2 ,3 ]
Rivest, Serge [1 ,2 ]
机构
[1] Laval Univ, Fac Med, Neurosci Lab, CHU Quebec Res Ctr, 2705 Laurier Blvd, Quebec City, PQ G1V 4G2, Canada
[2] Laval Univ, Fac Med, Dept Mol Med, CHU Quebec Res Ctr, 2705 Laurier Blvd, Quebec City, PQ G1V 4G2, Canada
[3] Laval Univ, Fac Med, Lab Innate Immun, CHU Quebec Res Ctr, 2705 Laurier Blvd, Quebec City, PQ G1V 4G2, Canada
关键词
NOD2; receptor; Monocytes; Microglia; Macrophages; Alzheimer's disease; Immunotherapy; Brain blood vessels; Cerebral amyloid angiopathy; Synapse; PASSIVE-AVOIDANCE TASK; AMYLOID-BETA PEPTIDE; SYNAPSE LOSS; IN-VIVO; CLEARANCE; BRAIN; PROTEIN; NOD2; MICROGLIA; LRP1;
D O I
10.1186/s12974-020-01893-3
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Background Muramyl dipeptide (MDP) is a component derived from minimal peptidoglycan motif from bacteria, and it is a ligand for the NOD2 receptor. Peripheral administration of MDP converts Ly6C(high)into Ly6C(low)monocytes. Previously, we have shown that Ly6C(low)monocytes play crucial roles in the pathology of a mouse model of Alzheimer's disease (AD). However, medications with mild immunomodulatory effects that solely target specific monocyte subsets, without triggering microglial activation, are rare. Methods Three months old APP(swe)/PS1 transgenic male mice and age-matched C57BL/6 J mice were used for high frequency (2 times/week) over 6 months and low frequency (once a week) over 3 months of intraperitoneally MDP (10 mg/kg) administrations. Flow cytometry analysis of monocyte subsets in blood, and behavioral and postmortem analyses were performed. Results Memory tests showed mild to a strong improvement in memory function, increased expression levels of postsynaptic density protein 95 (PSD95), and low-density lipoprotein receptor-related protein 1 (LRP1), which are involved in synaptic plasticity and amyloid-beta (A beta) elimination, respectively. In addition, we found monocyte chemoattractant protein-1(MCP-1) levels significantly increased, whereas intercellular adhesion molecule-1(ICAM-1) significantly decreased, and microglial marker (Iba1) did not change in the treatment group compared to the control. In parallel, we discovered elevated cyclooxygenase-2 (COX2) expression levels in the treated group, which might be a positive factor for synaptic activity. Conclusions Our results demonstrate that MDP is beneficial in both the early phase and, to some extent, later phases of the pathology in the mouse model of AD. These data open the way for potential MDP-based medications for AD.
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页数:12
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共 51 条
  • [1] Blood Monocytes: Development, Heterogeneity, and Relationship with Dendritic Cells
    Auffray, Cedric
    Sieweke, Michael H.
    Geissmann, Frederic
    [J]. ANNUAL REVIEW OF IMMUNOLOGY, 2009, 27 : 669 - 692
  • [2] Prostaglandin E2 and microsomal prostaglandin E synthase-2 expression are decreased in the cyclooxygenase-2-deficient mouse brain despite compensatory induction of cyclooxygenase-1 and Ca2+-dependent phospholipase A2
    Bosetti, F
    Langenbach, R
    Weerasinghe, GR
    [J]. JOURNAL OF NEUROCHEMISTRY, 2004, 91 (06) : 1389 - 1397
  • [3] Epigenetic editing of the Dlg4/PSD95 gene improves cognition in aged and Alzheimer's disease mice
    Bustos, Fernando J.
    Ampuero, Estibaliz
    Jury, Nur
    Aguilar, Rodrigo
    Falahi, Fahimeh
    Toledo, Jorge
    Ahumada, Juan
    Lata, Jaclyn
    Cubillos, Paula
    Henriquez, Berta
    Guerra, Miguel V.
    Stehberg, Jimmy
    Neve, Rachael L.
    Inestrosa, Nibaldo C.
    Wyneken, Ursula
    Fuenzalida, Marco
    Hartel, Steffen
    Sena-Esteves, Miguel
    Varela-Nallar, Lorena
    Rots, Marianne G.
    Montecino, Martin
    van Zundert, Brigitte
    [J]. BRAIN, 2017, 140 : 3252 - 3268
  • [4] Clearance of Amyloid-β Peptide Across the Blood-Brain Barrier: Implication for Therapies in Alzheimer's Disease
    Deane, R.
    Bell, R. D.
    Sagare, A.
    Zlokovic, B. V.
    [J]. CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS, 2009, 8 (01) : 16 - 30
  • [5] SYNAPSE LOSS IN FRONTAL-CORTEX BIOPSIES IN ALZHEIMERS-DISEASE - CORRELATION WITH COGNITIVE SEVERITY
    DEKOSKY, ST
    SCHEFF, SW
    [J]. ANNALS OF NEUROLOGY, 1990, 27 (05) : 457 - 464
  • [6] Synaptic trafficking of glutamate receptors by MAGUK scaffolding proteins
    Elias, Guillermo M.
    Nicoll, Roger A.
    [J]. TRENDS IN CELL BIOLOGY, 2007, 17 (07) : 343 - 352
  • [7] Blood monocytes consist of two principal subsets with distinct migratory properties
    Geissmann, F
    Jung, S
    Littman, DR
    [J]. IMMUNITY, 2003, 19 (01) : 71 - 82
  • [8] Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection
    Girardin, SE
    Boneca, IG
    Viala, J
    Chamaillard, M
    Labigne, A
    Thomas, G
    Philpott, DJ
    Sansonetti, PJ
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (11) : 8869 - 8872
  • [9] The Innate Immune Protein Nod2 Binds Directly to MDP, a Bacterial Cell Wall Fragment
    Grimes, Catherine Leimkuhler
    Ariyananda, Lushanti De Zoysa
    Melnyk, James E.
    O'Shea, Erin K.
    [J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2012, 134 (33) : 13535 - 13537
  • [10] Water T-maze: A useful assay for determination of repetitive behaviors in mice
    Guariglia, Sara Rose
    Chadman, Kathryn K.
    [J]. JOURNAL OF NEUROSCIENCE METHODS, 2013, 220 (01) : 24 - 29