Abstract
Alzheimer’s disease is the first common form of dementia worldwide. This neurodegenerative pathology is characterized by two main features in the brain: the extracellular aggregation of β-amyloid peptides, and the intraneuronal aggregation of abnormally phosphorylated Tau proteins. The gut microbiota, that has recently emerged has a key player in the function of the central nervous system, through the so-called gut-brain-axis, may be also implicated in the development and progression of Alzheimer’s disease. Studies on preclinical murine models have demonstrated a correlation between the composition of the gut microbiota and the brain amyloidosis. The objective of this thesis was to modulate the composition of the intestinal microbiota in the 5XFAD mouse model of amyloidosis, in order to evaluate the role of the bacterial component in the development of the pathology. This modulation of the microbiota has been carried out by classical microbial modulators such as antibiotics and prebiotics, and by gut microbiota transplantations. In parallel, therapeutical approaches aiming at developing multi-target directed ligands have emerged as Alzheimer’s disease is a complex and heterogeneous disease. Such compounds have been synthetized within the team and have been the subject of in-vivo evaluations. This thesis work has demonstrated on the one hand the promising results of a triple-activity compound to slow down the cognitive impairments and pathological alterations of the 5XFAD model, and on the other hand that the modulation of the gut microbiota of this model through pharmacological compounds, classical microbial modulators or fecal microbiota transplantation could offer new therapeutic avenues to treat Alzheimer’s disease.