Muramyl Dipeptide Administration Delays Alzheimer's Disease Physiopathology via NOD2 Receptors.

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.

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

Multiple sclerosis and Alzheimer's disease are two complex neurodegenerative diseases involving the immune system. So far, available treatments provide at best mild improvements to patients' conditions. For decades now, a new set of molecules have been used to modulate and regulate the innate immunity in these pathologies. Most studies have been carried out in rodents and some of them have reported tremendous beneficial effects on the disease course. The modulation of innate immune cells is of great interest since it provides new hope for patients. In this review, we will briefly overview the therapeutic potential of some molecules and receptors in multiple sclerosis and Alzheimer's disease and how they could be used to exploit new therapeutic avenues.

Transport of PEGylated-PLA nanoparticles across a blood brain barrier model, entry into neuronal cells and in vivo brain bioavailability.

Treatments of neurodegenerative diseases (NDDs) are severely hampered by the presence of the blood-brain barrier (BBB) precluding efficient brain drug delivery. The development of drug nanocarriers aims at increasing the brain therapeutic index would represent a real progress in brain disease management. PEGylated polyester nanoparticles (NPs) are intensively tested in clinical trials for improved drug delivery. Our working hypothesis was that some surface parameters and size of NPs could favor their penetration across the BBB and their neuronal uptake. Polymeric material PEG-b-PLA diblocks were synthesized by ring opening polymerisation (ROP) with PEG2000 or PEG5000. A library of polymeric PEG-b-PLA diblocks NPs with different physicochemical properties was produced. The toxicity, endocytosis and transcytosis through the brain microvascular endothelial cells were monitored as well as the neuronal cells uptake. In vitro results lead to the identification of favourable surface parameters for the NPs endocytosis into vascular endothelial cells. NPs endocytosis took place mainly by macropinocytosis while transcytosis was partially controlled by their surface chemistry and size. In vivo assays on a zebrafish model showed that the kinetic of NPs in circulation is dependent on PEG coating properties. In vivo findings also showed a low but similar translocation of PEG-b-PLA diblocks NPs to the CNS, regardless of their properties. In conclusion, modulation of surface PEG chain length and NPs size impact the endocytosis rate of NPs but have little influence on cell barriers translocation; while in vivo biodistribution is influenced by surface PEG chain density.