The Impact of the Adaptive Immune System on Alzheimer’s Disease Pathogenesis

Alzheimer’s disease (AD) in the most common neurodegenerative disorder in the world, affecting over 35 million people. AD is characterized by a progressive loss of memory and cognitive function that eventually robs patients of the ability to perform basic daily functions. However, currently approved therapies are not disease modifying and only provide limited benefits. Pathologically, the brains of AD patients exhibit two hallmark protein aggregates, amyloid plaques and neurofibrillary tangles composed of the protein tau.An additional pathological hallmark of Alzheimer’s disease is the presence of reactive microglia that surround plaques, contributing to a chronic proinflammatory state within the brain which exacerbates many of the other pathologies and cognitive symptoms that occur in AD. While the role of innate immunity in this process has been extensively studied, the potential influence of adaptive immunity in AD remains unclear. Yet growing evidence that cross-talk between adaptive and innate immunity occurs in both health and disease, led me to hypothesize that the peripheral adaptive immune system also plays a critical role in the pathogenesis of AD.The goal of my dissertation is to therefore determine the contributions of the adaptive immune system to the pathogenesis of AD. To achieve these goals, we created a novel AD mouse model (Rag-5xfAD mice), that, exhibits many of the hallmark pathologies of AD yet lacks the principal components of the adaptive immune system, B- and T-cells, and also lacks NK cells, considered a component of both adaptive and innate immunity.During my studies, I have uncovered that loss of the adaptive immune results in both a dramatic increase in amyloid pathology and a worsening of the chronic inflammatory state of the CNS compared to immune-intact AD mice. I have also demonstrated for the first time that non-specific B cell-produced antibodies are part of a critical regulatory mechanism that limits amyloid deposition in immune-intact animals. Taken together these results demonstrate that the adaptive immune system plays several critical roles in the pathogenesis of AD and suggests that further studies are needed to fully understand the complex interactions between innate and adaptive immunity that contribute to AD pathogenesis