Neurological Disease Researchers Confirm Link Between Adaptive Immune System and Alzheimer's Disease

Using a novel immunodeficient mouse model that they had created, a team of neurological disease researchers demonstrated the link between the adaptive immune system and the development of Alzheimer's disease.

While neuroinflammation and activation of innate immunity are pathological hallmarks of Alzheimer’s disease (AD), very few studies have examined the impact of the adaptive immune system on the progression of AD. To clarify this matter, investigators at the University of California, Irvine (USA) generated an immunodeficient AD mouse model that lacked T-, B-, and natural killer (NK) cells.

They reported in the February 16, 2016, online edition of the journal Proceedings of the National Academy of Sciences of the United States of America (PNAS) that these "Rag-5xfAD" mice exhibited a greater than twofold increase in beta-amyloid (A-beta) pathology. Gene expression analysis of the brain implicated altered innate and adaptive immune pathways, including changes in cytokine/chemokine signaling and decreased Ig-mediated processes. Neuroinflammation was also greatly exacerbated in the Rag-5xfAD mice as indicated by a shift in microglial phenotype, increased cytokine production, and reduced phagocytic capacity.

In contrast, immune-intact 5xfAD mice exhibited elevated levels of nonamyloid reactive IgGs in association with microglia, and treatment of Rag-5xfAD mice or cultures of their microglial cells with preimmune IgG enhanced A-beta clearance. In addition, bone marrow transplantation studies in Rag-5xfAD mice revealed that replacement of these missing adaptive immune populations could dramatically reduce AD pathology.

"We were very surprised by the magnitude of this effect," said senior author Dr. Mathew Blurton-Jones, assistant professor of neurobiology and behavior at the University of California, Irvine. "We expected the influence of the deficient immune system on Alzheimer's pathology to be much more subtle. We know that the immune system changes with age and becomes less capable of making T- and B-cells, so whether aging of the immune system in humans might contribute to the development of Alzheimer's is the next big question we want to ask."

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