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. 2020 Jul 22;17(1):218.
doi: 10.1186/s12974-020-01893-3.

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

Adham Fani Maleki  1 , Giulia Cisbani  1 , Marie-Michèle Plante  1 , Paul Préfontaine  1 , Nataly Laflamme  1 , Jean Gosselin  2 , Serge Rivest  3
Affiliations

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

Adham Fani Maleki et al. J Neuroinflammation. .

Abstract

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 Ly6Chigh into Ly6Clow monocytes. Previously, we have shown that Ly6Clow 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 APPswe/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 (Aβ) 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.

Keywords: Alzheimer’s disease; Brain blood vessels; Cerebral amyloid angiopathy; Immunotherapy; Macrophages; Microglia; Monocytes; NOD2 receptor; Synapse.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Regulation of monocyte subsets and a slight improvement in memory function following chronic MDP administration over 6 months (high frequency) in APP mice. a Representative timeline of chronic MDP administration over 6 months (high frequency) in APP mice, n = 10 mice per group. b Percentage of blood inflammatory Ly6Chi monocytes at two time points (3 and 6 months) following chronic MDP administration over 6 months (high frequency) in APP mice. Data are expressed as the means ± SEM; ***P < or = 0.0004 vs. APP vehicle in 3 months, ###P < or = 0.0004 vs. APP vehicle in 6 months. c Percentage of blood Ly6Clow patrolling monocytes at two time points (3 and 6 months) following chronic MDP administration over 6 months (high frequency) in APP mice. Data are expressed as the means ± SEM; ***P < or = 0.0004 vs. APP-MDP in 3 months, ###P < or = 0.0004 vs. APP-MDP in 6 months. d The total number of errors made on day 1 (D1), day 2 (D2), and day 3 (D3) in APP-MDP and APP-vehicle groups in learning performance in position habit acquisition at the two time points (3 and 6 months). Data analyzed using two-way ANOVA for the time points and treatments. e The total number of errors made on day 1 (D1), day 2 (D2), and day 3 (D3) in APP-MDP and APP-vehicle groups in learning performance in reversal learning training at the two time points (3 and 6 months). Data analyzed using two-way ANOVA for the time points and treatments. f Percentage of mice in APP-MDP and APP-vehicle groups made errorless trials in day 1 in reversal learning training at the two time points (3 and 6 months). g Average of total errors in APP-MDP and APP-vehicle groups in learning performance in reversal learning training at the two time points (3 and 6 months). Data analyzed using two-way ANOVA for the time points and treatments
Fig. 2
Fig. 2
Regulation of monocyte subsets and improvement in memory deficits following chronic MDP administration over 3 months (low frequency) in APP mice. a Representative timeline of chronic MDP administration over 3 months (low frequency) in APP and WT mice, APP n = 10 mice per group, and WT n = 5 mice per group. b, c Absolute count of blood inflammatory Ly6Chi monocytes in WT and APP mice and following chronic MDP administration over 3 months (low frequency). Data are expressed as the means ± SEM; $P < or = 0.01 vs. WT-vehicle. c Absolute count of blood Ly6Clow monocytes in WT and APP mice and following chronic MDP administration over 3 months (low frequency). Data are expressed as the means ± SEM; $$P < or = 0.003 vs. WT-MDP, %%P < or = 0.007 vs APP-MDP. d The total number of errors made on day 1 (D1), day 2 (D2), and day 3 (D3) in WT and APP mice in learning performance in position habit acquisition following chronic MDP administration over 3 months (low frequency). Data are expressed as the means ± SEM; ++P < or = 0.002 vs. WT-vehicle D1, **P < or = 0.003 vs. APP-MDP D1, ***P < or = 0.0004 vs APP-MDP D1. Data analyzed using two-way ANOVA for the time points and treatments. e The total number of errors made on day 1 (D1), day 2 (D2), and day 3 (D3) in WT and APP mice in reversal performance in position habit acquisition following chronic MDP administration over 3 months (low frequency). Data are expressed as the means ± SEM; ¥P < or = 0.0266 vs. APP-vehicle D2 and D3, ++++P < or = 0.0001 vs. WT-vehicle D1, ^^^^P < or = 0.0001 vs. WT-MDP D1, %P < or = 0.0092 vs. APP-vehicle D1, ***P < or = 0.0008 vs. APP-MDP D1. Data analyzed using two-way ANOVA for the time points and treatments
Fig. 3
Fig. 3
MDP treatment had no effect on microglial activation, and APP levels, but upregulated COX2 levels in APP mice. a Immunoblot analysis of APP levels in the cortex and hippocampus of APP mice treated with vehicle and MDP. b, c Immunoblot analysis of Iba1 and TREM2 levels in the cortex and hippocampus of APP mice treated with vehicle and MDP. d Immunoblot analysis of COX2 levels in the cortex and hippocampus of APP mice treated with vehicle and MDP. Data are expressed as the means ± SEM; ***P < 0.0001 vs. APP-MDP
Fig. 4
Fig. 4
Effect of MDP treatment on key proteins involved in synaptic functions, Aβ vascular clearance, and cerebrovascular monocyte adhesion. a, b Immunoblot analysis of synaptophysin and PSD95 protein levels, respectively, in the cortex and hippocampus of APP mice treated with vehicle and MDP, n = 10 mice per group. Data are expressed as the means ± SEM; *P < or = 0.03. c, d Immunoblot analysis of LRP1 and MCP-1 protein levels respectively in the cortex and hippocampus of APP mice treated with vehicle and MDP, n = 10 mice per group. Data are expressed as the means ± SEM; *P < or = 0.03. e, f Immunoblot analysis of VCAM and ICAM-1 protein levels, respectively, in the cortex and hippocampus of APP mice treated with vehicle and MDP, n = 10 mice per group. Data are expressed as the means ± SEM; ****P < or = 0.0001
Fig. 5
Fig. 5
A scheme summarizing MDP-mediated immunomodulatory effects on the APP mouse model of AD via converting inflammatory monocytes into patrolling monocytes. MDP treatments improved cognitive declines and Aβ clearance in APP mice and increased expression levels of PSD95 and LRP1 receptors
See this image and copyright information in PMC

References

    1. Girardin SE, Boneca IG, Viala J, Chamaillard M, Labigne A, Thomas G, et al. Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J Biol Chem. 2003;278(11):8869–8872. - PubMed
    1. Grimes CL, Ariyananda LDZ, Melnyk JE, O’Shea EK. The innate immune protein Nod2 binds directly to MDP, a bacterial cell wall fragment. J Am Chem Soc. 2012;134(33):13535–13537. - PMC - PubMed
    1. Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature. 2001;411(6837):603. - PubMed
    1. Auffray C, Sieweke MH, Geissmann F. Blood monocytes: development, heterogeneity, and relationship with dendritic cells. Annu Rev Immunol. 2009;27. - PubMed
    1. Guilliams M, Mildner A, Yona S. Developmental and functional heterogeneity of monocytes. Immunity. 2018;49(4):595–613. - PubMed

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