L'influence du Muramyl-Dipeptide sur la modulation de l'immunité innée dans la pathologie d'Alzheimer

Authors: Piec, Pierre-Alexandre
Advisor: Rivest, Serge
Abstract: Alzheimer's disease (AD) is the most common complex and multifactorial neurodegenerative disease in our society. It causes dysregulation of the innate immune system, resulting in degeneration of the brain environment and major cognitive problems, such as personality changes, apathy and language problems. This pathology is due, among other things, to the accumulation of a neurotoxic peptide, amyloid beta (Aβ), in the parenchyma and particularly in the blood vessels of the brain. In recent years, new therapeutic avenues have been investigated to delay symptoms and potentially cure Alzheimer's. Among them, the modulation of innate immune cells is of great interest because it offers a new hope to patients. This modulation is mainly peripheral through monocyte population conversion to a therapeutic phenotype of interest. The experiments and results presented in this master thesis aim to characterize the sex differences of the muramyl dipeptide (MDP) therapeutic pathway in AD-targeted monocyte conversion. Different studies have indicated the strong immunomodulatory power of MDP passed through the NOD2 receptor. We used the APP[subscript swe]/PS1 transgenic model mimicking the genetic form of Alzheimer's disease. For the characterization on APP[subscript swe]/PS1 mice, we administered MDP on these mice from 3 to 6 months to evaluate the preventive therapeutic effect against Aβ plaque formation. Thus, we have further characterized the changes caused by MDP on monocyte populations in healthy and NOD2[superscript -/-] mice. First, we were able to determine that the dose necessary to allow maximal monocyte conversion was 10mg/kg and that the administration named induction/priming (1 injection per day for 3 days) was necessary to start the monocyte stimulation and it is maintained at more than 5 days post-induction. In a second step, in Alzheimer mice, the administration of MDP delayed the onset of AD symptoms in both sexes, with a decrease in beta amyloid load, preservation of cognitive faculties, integrity of the blood-brain barrier (BBB), basal membrane (BM), an increase in phagocytosis and brain anti-inflammatory markers with a stimulated clearance system for an adequate peripheral elimination. However, female mice only showed a delay in AD symptoms, improved cognition, and BBB.
Document Type: Mémoire de maîtrise
Issue Date: 2022
Open Access Date: 25 July 2022
Permalink: http://hdl.handle.net/20.500.11794/73932
Grantor: Université Laval
Collection:Thèses et mémoires

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