Muramyl Dipeptide Administration Delays Alzheimer’s Disease Physiopathology via NOD2 Receptors

Abstract

Alzheimer’s disease (AD) is the most common form of dementia in the world. The prevalence is steadily increasing due to an aging population and the lack of effective treatments. However, modulation of innate immune cells is a new therapeutic avenue, which is quite effective at delaying disease onset and improving cognitive decline. Methods: We studied the effect of the NOD2 receptor ligand muramyl dipeptide (MDP) on the modulation of the innate immune cells, namely patrolling monocytes and microglia. We administrated MDP once a week for 3 months in an APPswe/PS1 mouse model in both sexes. We started the treatment at 3 months before plaque formation and evaluated its effects at 6 months. Results: We showed that the MDP injections delay cognitive decline in both sexes via different mechanisms and protect the blood brain barrier (BBB). In males, MDP triggers the sink effect from the BBB, leading to a diminution in the amyloid load in the brain. This phenomenon is underlined by the increased expression of phagocytosis markers such as TREM2, CD68, and LAMP2 and a higher expression of ABCB1 and LRP1 at the BBB level. The beneficial effect seems more restricted to the brain in females treated with MDP, where microglia surround amyloid plaques and prevent the spreading of amyloid peptides. This phenomenon is also associated with an increase in TREM2 expression. Interestingly, both treated groups showed an increase in Arg-1 expression compared to controls, suggesting that MDP modulates the inflammatory response. Conclusion: These results indicate that stimulation of the NOD2 receptor in innate immune cells is a promising therapeutic avenue with potential different mechanisms between males and females.

Vaccines and Dementia: Part II. Efficacy of BCG and Other Vaccines Against Dementia

“…By contrast, we have glimpses that molecular adjuvants might be of significant benefit in AD. MDP administration in AD model mice is reported to delay AD-related pathology [ 64 ]. Another adjuvant molecule, the CpG oligodeoxynucleotide 2006 (CpG ODN), has shown promise in mouse AD models [ 65 ] and produced favorable reductions in naturally occurring amyloid pathology in elderly squirrel monkeys [ 66 ]; clinical trials are planned in New York (NCT05606341).…”

The Synergistic Potential of Combining PD-1/PD-L1 Immune Checkpoint Inhibitors with NOD2 Agonists in Alzheimer’s Disease Treatment

“…They demonstrated that patrolling monocytes were the primary phagocytic cells responsible for clearing Aβ from the brain, suggesting that these cells may play an important role in the pathogenesis of AD [ 12 ]. These studies were recently reviewed by us [ 6 ]. Taken together, these studies suggest that patrolling monocytes have a unique ability to phagocytose cellular debris and foreign material in a variety of tissues, including the brain vascular system.…”

“…The recruitment of patrolling monocytes to vascular amyloid deposits is still not fully understood, but it is believed that CCR2, CCR5, and CX3CR1 each are partially involved in their recruitment [ 14 , 15 ]. Additionally, the intravital two-photon microscopy of our laboratory has demonstrated that patrolling monocytes are specifically attracted to the luminal wall of Aβ-positive vasculatures, and their removal has been shown to lead to a significant decrease in Aβ plaques [ 6 ]. This suggests that increasing the number of patrolling monocytes in the vasculature could be a potential therapeutic avenue for AD.…”

“…However, there may be some differences in the specific signaling pathways and downstream effects of these markers in mice and humans. The proliferation, differentiation, and migration of monocytes has been already reviewed in our previously published paper [ 6 ].…”

“…Over the last decade, the studies of our laboratory uncovered the crucial role of Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) in the function of monocytes. Indeed, we showed the activation of NOD2 receptors in the function of monocytes as a key switch for monocyte conversation from classical to patrolling monocytes in murine models of AD [ 6 , 7 ], as well as autoimmune diseases of multiple sclerosis (MS) [ 8 ], which contribute to the clearance of toxic amyloid beta (also known as Aβ), a hallmark of AD, and myelin debris in MS. The switch of monocyte conversation from classical to patrolling monocytes in response to NOD2 signaling was shown to play a powerful beneficial role in engulfing the toxic Aβ from the luminal side of the cerebrovascular system, which finally leads to improvement in AD symptoms.…”