Every 67 seconds, someone in the United States develops Alzheimer’s disease, a common form of dementia that slowly erodes a person’s memory and thinking skills until they no longer remember how to perform basic functions or recognize a loved one’s face.
For decades, researchers have worked to find ways to prevent the disorder, and while treatments exist to slow the disease’s progression and manage symptoms, there is no cure.
Now, a CU researcher is exploring a novel idea: the brain’s energy supply may be the missing link in preventing Alzheimer’s disease. Kimberly Bruce, PhD, associate professor in the University of Colorado Department of Medicine’s Division of Endocrinology, Metabolism, and Diabetes, is studying how a specific enzyme in the brain — one that helps metabolize fats — might play a role in stopping the disease before it starts.
“Metabolism is intrinsically linked to some of the strongest drivers of Alzheimer's,” Bruce says. “But it’s also potentially a modifiable factor.”
Our bodies rely on a process called lipid metabolism to turn fats into energy and manage how they’re stored or broken down. But if this system starts to malfunction, cells can become overworked — and that kind of imbalance may play a key role in the development of diseases like Alzheimer’s.
To better understand why this happens, Bruce has been studying an enzyme called lipoprotein lipase, which breaks down fat throughout the body, including in the brain.
“I was researching its role in other diseases and noticed that quite a few papers mentioned that this enzyme is increased in Alzheimer's disease,” Bruce says. “And I thought, well, that's our favorite enzyme. We need to try to figure out what it is doing.”
What Bruce and her team realized is that the enzyme is expressed in a specific type of cell called microglia. Bruce says these cells “act a bit like garbage collectors in the brain” by taking out the trash to make sure the brain stays healthy. This takes a lot of energy, which the cells get through fat or sugar metabolism.
“The analogy I use is that these cells are a bit like marathon runners,” Bruce says. “They’re using a lot of fat to slowly, steadily do all their important jobs in the brain to keep it healthy. But what happens in Alzheimer's disease and in aging is that these cells tend to switch towards using more sugar, a little bit like a sprinter.”
Using sugar for energy is essential to keep a person healthy and properly fueled. But in Alzheimer’s disease, these cells get stuck in “sprinter mode” and can’t return to their fat-burning state.
“If you were to ask a marathon runner to keep running for a long time, they can keep going,” Bruce says. “That's exactly what they’re supposed to do. But if you ask a sprinter to keep going for a long time, they’re going to become exhausted quickly.
“Our lab is trying to figure out why these microglial cells are getting stuck. We want to know why they’re using too much sugar and not enough lipids and then understand the mechanisms behind this so we can restore these cells to a balanced state.”
Bruce’s lab is exploring three risk factors that may contribute to the inability of microglial cells to switch back and forth from fat to sugar burning: low estrogen, a gene called APOE4, and high-fructose diets.
Around twice as many women have Alzheimer’s disease compared to men, and it’s hypothesized that declining levels of estrogen after menopause play a large role.
“When you lose estrogen, your cells lose the ability to break down fats into energy, so they switch to sugar,” Bruce says. “That’s what we think is happening in women, so we’re trying to figure out a way that we can mimic estrogen’s effects on metabolism to prevent Alzheimer’s disease.”
Another underlying cause of Alzheimer’s is genetic — a variant of the APOE gene, called APOE4. There are three different types of APOE, which provide cells with instructions on how to make lipoproteins that transport cholesterol and fats throughout the body. It’s estimated that people who carry two APOE4 copies, one from each parent, have a 60% chance of developing Alzheimer’s by age 85. And while only 2% of the population carry this gene, they make up about 15% of all Alzheimer’s cases.
“APOE is needed to carry lipids around the brain, but APOE4 is not as good at doing its job compared to other types of APOE,” Bruce says. “So, what happens if you can't get fat into the cell? It has to switch to using sugars as an alternative energy source. We're trying to think about ways in which we can stop APOE4 from performing poorly.”
Another arm of her lab’s research focuses on fructose metabolism in microglial cells, which has been shown to increase features of Alzheimer’s disease. Her team is looking at the specific mechanism that cells use to process fructose and how that might contribute to the disease. They’ve conducted several tests that suggest that if fructose metabolism is shut down in a cell, it improves microglial function.
“Of course, someone might ask, ‘Why don't you just not eat a fructose diet?’” Bruce says. “But we've been exposed to high-fructose diets since childhood. It’s in everything from your breakfast cereal to snacks and frozen dinners. Throughout your life, you’ve powered up all the cellular machinery that processes fructose. Yes, you can take away fructose, but you may also need help powering down that machinery as well.”
While her team continues to work on further understanding and developing interventions for these Alzheimer’s risk factors, they are also moving forward with another development — small molecules that increase the function of enzymes, which allow cells to gain more energy.
They discovered this by running tests that eliminated lipoprotein lipase — Bruce’s favorite enzyme — from cells. They realized that when they got rid of it, cells switched into the exhausted sugar-burning sprinter state.
“So, we thought, it's obviously a good guy and is needed in these cells,” Bruce says. “From there, we wanted to develop something that could increase its activity to improve cell function.”
Her team looked through literature and realized there was already a naturally available activator for the enzyme — a protein called APOC2. They were able to isolate a specific part of the protein that binds to lipoprotein lipase and run experiments to figure out how the mechanisms work.
“We figured out that APOC2 stabilizes this enzyme and makes it active,” Bruce says. “And now, we’re taking this particular peptide, which is based off a natural protein that exists in the body, and packaging it in such a way that it's an even more profound activator and has better access to the brain.”
Bruce’s lab has a National Institutes of Health RO1 grant that has propelled much of her work. Her next steps are securing patents and funding for preclinical development of these activators.
And while Bruce is working on these pharmacologic interventions, what can people do to reduce their risk of Alzheimer’s disease?
“Diet and lifestyle interventions are important for reducing the risk of any disease,” Bruce says. “That’s a huge take-home message. Even in the absence of having pharmacotherapeutics, limiting fructose consumption, especially in women and later in life, and exercising regularly, which has been shown to slow the progression of Alzheimer’s, can never really do any harm. So why not implement them now?”
Photo at top: Kimberly Bruce, PhD, second from left, with members of her team in her lab. Photo by Justin LeVett Photography.