Ready, Set, Grow Neurons: Working out the blood to reduce brain inflammation

The culture of fitness

Love it or hate it, there is no doubt that every time we exercise, we make our bodies a little bit stronger and a little bit healthier. Exercising is so deeply ingrained into our value system that entire industries have emerged and thrived around the promotion of health and fitness.

This certainly is no mistake, as substantial research has linked exercising ‒ especially running ‒ with better heart health, a more robust immune system, and improved brain function. In fact, scientists over the past decade have shown that routine exercise can markedly improve our mental capacity to learn and remember, in part by reducing inflammation in our brain.

But how exercise can affect the brain is a largely uncertain question, colored with many different theories. One idea that has floated around is that fitness can change the properties of our blood, and in turn protect our brain. A recent paper from Stanford University directly addresses this theory. Researchers transferred blood from exercising mice to non-exercising mice and saw that after the transfer, the non-exercisers exhibited reduced brain inflammation, improved growth of brain cells (or neurons), and enhanced learning and memory.

How can exercising reduce brain inflammation?

Normally, a microscopic structure called the blood-brain barrier acts as a fence protecting the brain from potentially harmful components of the blood, especially immune cells. However, during instances of brain inflammation, this barrier is dissolved and immune cells are allowed entry, which can wreak havoc if left unchecked. Traditionally, brain inflammation is caused by viral or bacterial infection. However, in certain conditions such as Alzheimer’s disease or aging, low levels of brain inflammation can worsen learning and memory, even in the absence of infection. Thus, determining how such inflammation may be managed can have critical clinical importance.

In the paper, Miguel et al. found that when mice exercise, an unknown component in the blood reduces inflammation in the brain. Specifically they saw that when non-exercising mice (“non-runners”) were given the blood of exercising mice (“runners”) they exhibited, in the brain, reduced levels of genes typically associated with an inflammatory process. The scientists further found increased growth of neurons in the hippocampus, the brain region famously known for processing learning and memory.

The scientists also wanted to demonstrate that these mice did in fact develop better learning and memory. To do this, they used a classic learning test known as the Morris water maze, in which mice are trained to find a hidden platform submerged underwater. When “non-runners” were given “runner” blood, the mice were much better at using clues in their environment to locate this platform, indicating better learning capacity.

Exercising “improves” our blood

To identify this unknown component in “runner” blood that confers learning power, the researchers used a technique known as mass spectrometry, which identifies and measures all proteins in a sample of blood. By comparing the blood of “runner” mice to “non-runners,” they noticed that the protein, clusterin (CLU), was highly elevated with exercise.

CLU is a helper protein that can remove toxic deposits of protein clusters, hence the name “clusterin.” However, over the past several decades, CLU has been described to have many additional roles in cell death, pain, cancer, and even inflammation. Coincidentally, several groups have already previously studied how CLU affects the progression of Alzheimer’s disease, with varying results. 

After noticing elevated CLU levels following exercise, the researchers set out to confirm CLU’s role in improved brain function. When they eliminated CLU from the blood of “runner” mice, the “runner” blood was no longer able to diminish brain inflammation in “non-runners.” This finding confirms that CLU is the blood-borne reason why exercise can enhance brain performance.

Clusterin as medicine

Interestingly, when the researchers injected artificially-produced CLU into mice with Alzheimer’s disease, they found a reduction in brain inflammation. Since ongoing brain inflammation is a well-accepted contributor to cognitive decline in Alzheimer’s disease, CLU may represent a new tool used to combat such a debilitating condition.

Finally, the researchers wanted to find evidence that exercise can be linked to CLU levels in humans. To do so, they analyzed the blood of veterans with mild amnesia before and after a 6-month fitness regimen. As expected, exercise resulted in a significant increase in CLU, confirming that these findings in mice may be applicable to humans as well. Well-controlled clinical studies will be needed to further determine if CLU can truly mitigate the cognitive symptoms of dementia in humans.

Figure 1. Mechanism that links exercise and brain protection. Mice that undergo exercise (“runners”) have increased levels of the protein CLU. When blood containing this protein is transfused into non-exercising mice (“non-runners”), CLU acts on the brain to reduce inflammation. In turn, specialized neurons of the hippocampus are allowed to grow and divide, resulting in overall improvements in learning and memory.

How to exercise without exercising

Through their experimental evidence, the scientists of this work have painted a uniquely exciting picture explaining why exercise is good for the brain. They identified a protein ‒ CLU ‒ that is elevated by exercise and helps the brain minimize inflammation, and by doing so, potentially improve brain function.

On a facetious note, the findings might suggest that by taking the blood of your more fit friend, you can reap the neurological rewards of exercise without ever touching a treadmill. Of course, the more powerful impact of these findings is the molecular confirmation of exercise as a brain-boosting method, notably in the context of dementia. CLU may further represent a unique therapy from which some dementia patients ‒ especially those afflicted with Alzheimer’s disease who may be intolerant of routine physical exertion ‒ could benefit.

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