The adaptive immune system restrains Alzheimer's disease pathogenesis by modulating microglial function
Significance 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. Here, we find that genetic ablation of peripheral immune cell populations significantly accelerates amyloid pathogenesis, worsens neuroinflammation, and alters microglial activation state. Critically, it appears that loss of IgG producing B cells impairs microglial phagocytosis, thereby exacerbating amyloid deposition. Conversely, replacement of IgGs via direct injection or bone marrow transplantation reverses these effects and reduces Ab pathology. Together, these results highlight the importance of the adaptive immune system and its interactions with microglia in the pathogenesis of AD. The innate immune system is strongly implicated in the pathogenesis of Alzheimer's disease (AD) In contrast, the role of adaptive immunity in AD remains largely unknown. However, numerous clinical trials are testing vaccination strategies for AD, suggesting that T and B cells play a pivotal role in this disease. To test the hypothesis that adaptive immunity influences AD pathogenesis, we generated an immune deficient AD mouse model that lacks T, B, and natural killer (NK) cells. The resulting "Rag 5xfAD" mice exhibit a greater than twofold increase in b amyloid (Ab) pathology. Gene expression analysis of the brain implicates altered innate and adaptive immune pathways, including changes in cytokine/chemokine signaling and decreased Ig mediated processes. Neuroinflammation is also greatly exacerbated in Rag 5xfAD mice as indicated by a shift in microglial phenotype, increased cytokine production, and reduced phagocytic capacity. In contrast, immune intact 5xfAD mice exhibit elevated levels of nonamyloid reactive IgGs in association with microglia, and treatment of Rag 5xfAD mice or microglial cells with preimmune IgG enhances Ab clearance. Last, we performed bone marrow transplantation studies in Rag 5xfAD mice, revealing that replacement of these missing adaptive immune populations can dramatically reduce AD pathology. Taken together, these data strongly suggest that adaptive immune cell populations play an important role in restraining AD pathology. In contrast, depletion of B cells and their appropriate activation by T cells leads to a loss of adaptive innate immunity cross talk and accelerated disease progression.
Proceedings of the National Academy of Sciences