Résumé
Alzheimer’s Disease (AD) is the most common form of dementia. It is characterized by behavioral deficits (e.g. memory loss) and histological features (e.g. β-amyloid deposits). Neuroinflammation is another important hallmark of the disease. When brain homeostasis is compromised, microglia, brain main immune cells, become reactive thus contributing to neuroinflammation. Almost all AD risk genes are highly expressed in microglia demonstrating their crucial role in this disorder. Whether microglia play beneficial and/or detrimental roles to the disease progression remains heavily debated and, in addition, their role at early stages of the pathology is still poorly understood.This study was designed to investigate the microglial reactivity at early stage of AD. The main objectives were to: (1) characterize whether early (prior to plaques seeding) microglial reaction occurs; (2) identify genes and pathways dysregulated in this early phase; and (3) determine whether these genes may represent potential early biomarkers.Using an AD mice model in which microglia express GFP (APPswe/PS1de9.CX3CR1+/eGFP mice), we isolated the parenchymal microglia at an early phase of the disease. RNA sequencing revealed significant remodeling of the microglial transcriptome and led to the identification of early markers of the pathology. We then focused on two genes representing potentially early biomarkers and investigated their expression in brain tissue from early stage AD mice. Using in-situ hybridization and immunohistochemical approaches, we demonstrate their upregulation in discrete microglial subpopulations. In parallel, we also demonstrate that, at this disease’s stage, synaptic modifications, microglial phenotypic reactivity and subtle cognitive alterations occur.As a whole our data support an early contribution of microglia to AD progression and point to specific genes that may represent potential early biomarkers and/or therapeutic targets.