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 3-months old APPswe/PS1 transgenic male mice and age-matched C57BL/6J mice were used for high frequency (2-times/week) over 6-months and low frequency (once a week) over a 3-months period of intraperitoneally MDP (10 mg/kg) administrations. Flow cytometry analysis of monocyte subsets in blood, behavioral and post mortem analyses were performed. Two-photon microscopy using APP/PS1/CX3CR1gfp/+ mice were conducted to study vascular Aβ clearance by Ly6Clow monocytes upon MDP administration.Results The treatment improved cognitive declines, increased expression levels of postsynaptic density protein 95 (PSD95) andlow 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 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. Following MDP treatment, intravital two-photon microscopy demonstrated that Ly6Clow monocytes are recruited into the brain vasculature in APP but not wild type mice, and they are able to pick up Aβ peptides. 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.
Muramyl dipeptide mediated immunomodulation on monocyte subsets exerts therapeutic effects in a mouse model of Alzheimer’s disease
