Etude du rôle de la sénescence cérébrale dans la pathogenèse de la maladie d'Alzheimer
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- Alzheimer's disease is a neurodegenerative disease characterized by two histological lesions, namely amyloid plaques (amyloid pathology) and neurofibrillary tangles (Tau pathology). Its main risk factor is aging which, at the molecular level, is based on a key biological process called cellular senescence. This is characterized by phenotypic alterations affecting the normal function of cells without leading to cell death. Telomere attrition is a major trigger. Although several studies demonstrate the link between brain senescence and neurodegenerative diseases such as Alzheimer’s disease, the underlying cellular and molecular mechanisms are not clearly established. Therefore, this project aims to determine the role of brain cellular senescence in the pathogenesis of Alzheimer’s disease, and in particular in amyloid pathology and neurodegeneration. To do so, we use a model of accelerated senescence (Terc-/-), lacking telomere maintenance, and a model of amyloid pathology (5xFAD) expressing five mutations found in inherited forms of Alzheimer’s disease. These two models are crossed, and we study markers of senescence (IL-6, IL-1beta, TNF-alpha and CXCL1), amyloid pathology (amyloid plaques, monomeric Abeta, intraneuronal Abeta) and neurodegeneration (synaptic function, neuronal density) in the brain of 1.5-, 2- and 5-months old mice. Our results show that telomere attrition, with or without amyloid pathology, increases inflammatory factors characteristic of senescent cells. Surprisingly, telomere attrition leading to cellular senescence also reduces the number of amyloid plaques and the levels of monomeric Abeta in 5xFAD mice at 5 months. This could be explained by an increase in glial activation (gliosis) at the same age and by an increase in intraneuronal Abeta sequestration at 1.5 and 2 months. No synaptic alterations are observed in our models, but amyloid pathology and telomere shortening seem to reduce neuronal density at 2 and – more strongly – at 5 months.