The Adaptive Immune System Restrains Alzheimer’s Disease (AD) Pathogenesis by Modulating Microglial Function

Neuroinflammation and activation of innate immunity are pathological hallmarks of Alzheimer’s disease (AD). In contrast, very few studies have examined the impact of the adaptive immune system in AD pathogenesis. In this study, we find that genetic deletion of peripheral immune populations significantly accelerates amyloid pathogenesis, worsens neuroinflammation, and alters microglial activation state. We used microarray analysis to profile gene expression underlying genotype related changes at the cellular level in the context of AD . To examine the impact of the adaptive immune system on AD pathogenesis, we backcrossed a well-established AD transgenic line, 5xfAD mice [Oakley et al., 2006], on to a Rag2-/-/Il2rγ-/- double knockout background, creating mice that lacked T-cells, B-cells, and NK-cells. In the process of generating these immune-deficient “Rag-5xfAD” and “Rag-WT” littermates, we also produced strain-matched equivalent immune-competent AD transgenic and wild-type mice termed “WT-5xfAD” and “WT-WT” respectively.