Alzheimer’s and the Inflamed Brain: Their Links Run Deeper than Thought

Given that Alzheimer’s disease (AD) is a brain disorder and the leading cause of dementia, it seems logical to assume that some sort of breakdown in the connections of the brain’s nerve cells is mostly to blame.

But based on an increasing volume of research, it turns out that our immune system is also closely linked in a negative way to the disease. Yes, the very same immune system that fights off infections from the bacteria and viruses we come in contact with everyday.

The brain’s local cleaning crew overwhelmed by beta-amyloid and Alzheimer’s
Like a foot soldier keeping watch over the castle for enemy invaders or internal traitors, immune cells called microglia that reside in the brain constantly survey the brain, and literally gobble up any potentially harmful “enemies”. This is true for the potentially harmful protein clumps called beta-amyloid plaques that form in the Alzheimer’s brain. But studies suggest the microglia’s clearance of beta-amyloid plaques gets overwhelmed in Alzheimer’s, shifting the cells’ activity into primarily an inflammation mode and leading to progressive damage to the brain.

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Microglia (green) surround an amyloid plaque (blue) in the brain of an Alzheimer’s disease mouse model. Image: Samuel Marsh/UC Irvine

Microglia (green) surround an amyloid plaque (blue) in the brain of an Alzheimer’s disease mouse model. UCI researchers have shown that endogenous mouse antibodies (red) associate with microglia in the brains of such mice and boost microglia’s ability to degrade plaques.
Samuel Marsh

Microglia represent the localized, first-responder arm of the immune system also called the innate immune system. A second wave, composed namely of immune cells called B cells and T cells, which targets the “enemy” with much more specificity, is initiated outside the brain. To what extent this so-called adaptive immune system is also linked to Alzheimer’s is less understood.

Now, scientists with the Sue & Bill Gross Stem Cell Research Center at the UC Irvine report in  PNAS that they have some answers.

Knocking out B and T cells makes matters worse
Beginning with a strain of mice that mimics Alzheimer’s symptoms with severe beta-amyloid plaque deposits in their brains, the research team bred the animals to also lack B and T cells. Six months later, the results were dramatic. The level of beta-amyloid plaques in AD mice without B and T cells was twice that of AD mice with an intact immune system. As Mathew Blurton-Jones, the team’s lead and UCI assistant professor (he’s also a CIRM-grantee though we did not fund this research), mentioned in a press release on Tuesday, this finding was unexpected:

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Mathew Blurton-Jones, assistant professor of neurobiology & behavior at UCI. Image: Steve Zylius / UCI

“We were very surprised by the magnitude of this effect. We expected the influence of the deficient immune system on Alzheimer’s pathology to be much more subtle.”

So what’s going on here? Why does knocking out the adaptive immune system in AD mice lead to even more beta-amyloid plaques? One hint came from a careful analysis of microglial cells in the brains of the AD mice lacking B and T cells. These cells showed a weakened “eating” activity compared to microglia in AD mice with an intact immune system. This result suggests that without B and T cells, the beta-amyloid plaques are not cleared away by microglial as well.

Additional experiments pointed to the importance of B cells on microglial function. First author Samuel March explained the result in the press release:

“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.”

Restoring beta-amyloid clean up with a blood stem cell transplant
So, in other words, eliminating B cells eliminates the recruitment of antibodies in the brain which in turn impairs the microglia’s ability to clear away beta-amyloid. To prove this point, the team transplanted healthy blood stem cells into the AD mice lacking B and T cells. The stem cells are capable of restoring all the cell types of the immune system. Sure enough, four months after the transplantation, antibodies were present in the brain near microglia and were associated with a nearly 50% reduction in beta-amyloid plaques.

All together, this data points to Alzheimer’s as a disease of an aging immune system, an idea that Blurton-Jones plans to tackle next:

“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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