Abstract
Alzheimer’s Disease (AD) is the most common form of dementia in the elderly. Effective threapeutics are still very needed for this neurodegenerative disorder. Interestingly, almost all risk genes for sporadic AD are highly expressed in microglia demonstrating their crucial role in this disorder.Microglial cells are brain resident immune cells. They play pivotal roles in neuroinflammatory processes. However, whether microglia play beneficial and/or detrimental roles in AD progression remains heavily debated and, in addition, their roles in the early stages of the pathology are still poorly understood.Previous study from our lab identified several microglial genes dysregulated in AD early stages. We focused our work on two main targets : Cst7 and Clec7a. Indeed, while the microglial roles of these two genes are poorly known, their peripheral functions (cytokines production, phagocytosis and protein degradation) put them under the spotlight for early involvment in AD.The main objectives of this thesis project were : (i) to caracterize AD early stage development in the APP(swe)/PS1(dE9) model; then (ii) to study the targets’ implication in AD initiation, (iii) to unravel their microglial functions, and finally (iv) to demonstrate their relevance in Humans.As a whole our data support an early contribution of microglia to AD progression in the APP(swe)/PS1(dE9) mouse model and point to two specific genes that may represent potential early biomarkers and/or therapeutic targets.