How Exercise Helps Fight Alzheimer’s Disease

(Posted on Tuesday, September 26, 2023)

A silent pandemic is underway. In 2016, 45 million people were affected by Alzheimer’s disease. By 2050, this number is expected to soar to 100 million. We have yet to develop successful treatment options and the exact causes remain nebulous. New research, published in the journal Neuron, cuts through some of the fog, providing novel avenues for treatment. Working out of Massachusetts General Hospital (MGH), Eunhee Kim and colleagues describe how a protein called irisin breaks down amyloid beta in the brain, one of the hallmarks of Alzheimer’s disease.

What is Amyloid Beta?

As we age, our brain shrinks. A small amount of shrinkage is normal and, despite the drop in brain “volume”, usually does not bring about a significant loss of neurons. With Alzheimer’s disease, the amount the brain shrinks is excessive. This is accompanied by a mass die-off of neurons and impaired neuronal function: communication and routine repairs begin to falter. 

Although the root cause —and there may be multiple— of Alzheimer’s disease has yet to be uncovered, there are two prime suspects: amyloid plaques and “tau tangles”. Amyloid plaques form when multiple protein fragments, known as amyloid beta, clump together. Over time, the abnormal collection of “sticky” proteins develops into a plaque, blocking up important signaling pathways and impairing memory formation.

Fighting Back with Exercise

Previous studies suggest physical activity and exercise have the potential to lessen amyloid beta buildup in the brain while also decreasing inflammation. The result? Improved cognitive health. But the mechanisms underlying the healing effects of exercise remained unknown. 

One potential explanation comes by way of a hormone released by our muscles during exercise: irisin. This small signaling molecule helps regulate glucose and fat metabolism in fatty tissues. It also boosts energy by converting white fat tissue into brown fat tissue — the former acts as a storage place of energy, like a battery, whereas the latter specializes in expending stored energy. Crucially, irisin is not held back by the blood-brain barrier and has been found throughout the brain, including the hippocampus, or “memory center”. Irisin levels were recently shown to be lower in the hippocampus and cerebrospinal fluid of Alzheimer’s patients compared to their healthy peers.

Irisin Reduces Amyloid Beta Deposits

To confirm whether irisin was behind the exercise-related improvements in cognitive function, the researchers turned to a three-dimensional model of Alzheimer’s disease they developed a few years prior. Instead of just simulating the cellular makeup of the brain, as is often the case with cell cultures grown on flat Petri dishes, the model they devised also simulates the three-dimensional structure, or “architecture”, of the brain. The additional dimension creates an environment that more closely resembles that of the brain itself, improving the veracity and predictive power of the results. 

The three-dimensional disease models exposed to irisin displayed an astonishing drop in amyloid beta deposits, directly implicating the molecule in the benefits to cognitive health associated with exercise.  Still, it wasn’t clear why this was happening: how does irisin lead to a breakdown of amyloid beta deposits? 

Further experiments revealed that irisin was binding to cells in the brain called astrocytes. These cells are the major cells of the central nervous system (CNS). Think of them like all-purpose caretakers; they provide the building blocks from which neurotransmitters are made, they get rid of any excess neurotransmitters, they clear abnormal debris, promote synapse formation, and regulate the blood-brain barrier. They also happen to secrete an enzyme called neprilysin, known to degrade amyloid beta and improve memory function in mice with Alzheimer’s disease. Indeed, neprilysin was being secreted by the astrocytes to which irisin had been binding. As in the other studies, the increase in neprilysin correlated with a decrease in amyloid-beta deposits. The researchers even managed to track down the precise surface receptor that allowed irisin to bind to the astrocytes: integrin αV/β5. 

One final discovery was that, to enhance neprilysin levels, irisin downregulates two critical signaling proteins: extracellular signal-regulated kinase (ERK)-signal transducer and activator of transcription 3 (STAT3).

Caveats

Three-dimensional cell-culture models have a clear edge over their two-dimensional counterparts, but they are still, ultimately, limited. The brain is a massively complex environment, and it will always be difficult to accurately mimic all of its nuances. Even animal models, usually considered one step above cell culture, often fail to accurately predict outcomes in humans. Despite the exciting results, we would do well not to get ahead of ourselves — until they are replicated in human trials, consider the findings groundwork for future studies.

Takeaways

Exercise has been known to decrease amyloid beta buildup in animals and humans with Alzheimer’s disease, boosting memory and improving cognitive health. How it was achieving this, however, was unclear. In their important findings, Eunhee Kim and colleagues have brought to light the mechanism underlying these cognitive benefits: irisin binds to astrocytes, which secrete an amyloid-degrading enzyme called neprilysin. This discovery opens the door to new directions for treatment, and possibly even prevention, of the disease. 

The research adds to a growing body of scientific literature underscoring the importance and benefits of physical activity to brain health. Along with irisin, platelet factor 4 and klotho have also been shown to promote cognitive function, including critical thinking and memory.