Abstract
Alzheimer’s Disease (AD) is the most common form of dementia. It is characterized by both behavioral deficits (e.g. memory loss) and histological features (e.g. β-amyloid deposits and Neurofibrillary Tangles). Neuroinflammation is also recognized as another important hallmark of the disease. The chain of events leading to AD has been the object of intense research for decades. Recently, human genetic studies revealed that microglia, which play key roles in neuroinflammation initiation, express many genes that represent significant risk factors in AD. Those findings support microglia as key contributors to AD pathogenesis. Yet, their contribution to the disease progression is still poorly understood. In particular, whether microglia play beneficial and/or detrimental roles in the disease progression remains heavily debated. One hypothesis to explain this potential duality of effects is that different subtypes of reactive microglia could play different functional roles.In AD, microglia clustered around amyloid-β plaques show altered phenotypes compared to those distant from the plaques, highlighting the diversity of microglia in this disease. However, the extent to which these two microglia subtypes molecularly and functionally differ remains largely unknown. In this study, we combined laser microdissection and RNA-seq approaches to decipher the roles of plaques-associated microglia and that of parenchymal microglia (i.e. microglia that are not associated with dense plaques). AD is a progressive neurodegenerative disorder, and to take this into account, transcriptional remodeling in the different microglia subtypes has been evaluated at both early, intermediate, and late stages of the disease. By combining WGCNA with GO & pathways analyses, we demonstrated that, as expected from their distinct morphology, plaques-associated microglia exhibit profound transcriptome changes. However, although parenchymal microglia exhibited a typical ramified homeostatic morphology, significant transcriptomic remodeling was also evidenced in this microglia subtype, even in the early stages of the disease when plaques barely form (i.e. 4-months-old APP/PS1 mice).As a whole, our data support a strong involvement of microglia during AD progression and highlight the differential contribution of parenchymal and plaques-associated microglia to the disease progression. In addition, they confirm that microglia reaction is involved in the early stage of the disease. Identification of microglia subtypes with specific functional roles opens the possibility to target one specific subtype with the aims of either promoting beneficial classes or hampering deleterious ones.