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

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 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 (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.

Triggering Innate Immune Receptors as New Therapies in Alzheimer’s Disease and Multiple Sclerosis

“…The study has shown a delayed cognitive decline associated with a stable increase in patrolling monocytes and a drastic diminution of inflammatory monocytes in the blood over time. Interestingly, the effect of repeated injections of MDP was still effective in six-month-old mice and we did not find health issues suggesting that the molecule is safe in mice even for three consecutive months [151]. These results also suggest that the cognitive improvement in the MDP group could be attributed to the sink effect since MDP-injected mice presented a higher expression level of LRP.…”

“…This receptor is able to transport amyloid through the blood-brain barrier and, interestingly, LRP1 expression is downregulated in AD [153,154]. The cognitive improvement is also associated with a higher expression of the synaptic marker PSD-95 compared to APP mice at six months [151]. Altogether, these results demonstrated a strong beneficial role of MDP in AD, but further studies are needed to unveil the underlying mechanisms.…”

“…Regulating the inflammatory response could also be a promising strategy in AD. Our group has recently demonstrated that repeated injections of MDP in a mouse model of AD from three months old to six months old once a week can prevent the appearance of symptoms [151]. We hypothesized that increasing the pool of patrolling monocytes could decrease the amyloid load in brain blood vessels by triggering a sink effect between the brain and the vasculature.…”

Monocyte Transmodulation: The Next Novel Therapeutic Approach in Overcoming Ischemic Stroke?

“…The second subset is known for alternative and non-classical activation, and it is characterized by an antiinflammatory phenotype and CX3CR1-dependent recruitment to local non-inflamed tissues; this subpopulation expresses Ly6C − CCR2 low CX3CR1 high markers (28)(29)(30). Blood monocytes have plasticity and are embroiled in pro-inflammatory and antiinflammatory responses in various diseases (28,(31)(32)(33)(34). Blood monocytes are a heterogeneous population of circulating leukocytes.…”

Danger-Sensing/Patten Recognition Receptors and Neuroinflammation in Alzheimer’s Disease

“…These data indicate that TLR-2 and NOD2 may play a relevant role in neuroinflammation and AD. On the other hand, the intraperitoneal administration (10 mg Kg −1 once or twice weekly) for three or six months of muramyl dipeptide (MDP), a NOD2 receptor ligand, to 3-month-old APP swe /PS1 transgenic male mice and, as controls, to age-matched C57BL/6J mice was beneficial under several respects with no concurrent microglial activation in both earlier and later phases of the neuropathology in AD-model mice [280].…”