Immune System May Play Greater Role in Alzheimer's Than Thought

While many studies have explored the role of microglia in Alzheimer’s, very few researchers have examined the role of the adaptive immune system.
While many studies have explored the role of microglia in Alzheimer’s, very few researchers have examined the role of the adaptive immune system.

Unexpected parts of the immune system may have a greater role in the development of Alzheimer's disease than previously thought, according to research published in the Proceedings of the National Academy of Sciences.

While many studies have explored the role of microglia — the main form of immune defense in the central nervous system (CNS)— in Alzheimer's disease, very few researchers have examined how the adaptive immune system may also impact Alzheimer's.

To test the role of the adaptive immune system in Alzheimer's, Mathew Blurton-Jones, PhD, assistant professor of neurobiology and behavior at the University of California, Irvine, doctoral student Samuel Marsh, and colleagues, bred genetically modified Alzheimer's disease mice to lack 3 different immune cell types: T-cells, B-cells, and NK-cells.

The researchers found that six months later, the brains of mice missing these three key immune cell types had more than twice as much beta-amyloid accumulation compared with the Alzheimer's mice with intact immune systems.

“We were very surprised by the magnitude of this effect,” Dr Blurton-Jones said in a statement. “We expected the influence of the deficient immune system on Alzheimer's pathology to be much more subtle.”

To understand how the loss of T-cells, B-cells, and NK-cells might be increasing levels of beta-amyloid, the researchers examined the interactions between these cells and microglia in the brain.

“We found that in Alzheimer's mice with intact immune systems, antibodies — which are made by B-cells — accumulated in the brain and associated with microglia. This, in turn, helped increase the clearance of beta-amyloid,” Marsh said.

The researchers then tested whether replacing these cells would reverse beta-amyloid buildup. They transplanted healthy bone marrow stem cells into the immune-deficiant Alzheimer's mice, which would lead to a reconstitution of the missing T, B, and NK-cells. They found that after replacing these cells, the B-cells could then once again produce antibodies that reached the brain and aided migroglia in eliminating beta-amyloid.

“Our study therefore adds to a growing area of research that highlights the importance of the peripheral immune system in CNS function and Alzheimer's disease, and demonstrates the need to better understand how these peripheral cell populations act in concert with microglia to influence the CNS in both normal and diseased conditions,” the researchers wrote.

“We know that the immune system changes with age and becomes less capable of making T and B-cells,” said Dr Blurton-Jones. “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.”

Reference

Marsh SE, Abud EM, Lakatos A, et al. The adaptive immune system restrains Alzheimer's disease pathogenesis by modulating microglial function. Proc Natl Acad Sci U S A. 2016; doi:10.1073/pnas.1525466113.

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