Decoding dementia

While many neurodegenerative diseases are classified as age-related illnesses, some influential factors are at play as early as conception. When a cell begins to specialize into one of the millions of options within the body, aspects of its destiny will follow a template based on instructions coded within its DNA.

The particulars of a cell’s design change due to typos while replicating the code. Some changes can protect against damage, while others may cause mutations that make a cell more susceptible to harm.

David Brafman, an associate professor of biomedical engineering in the Ira A. Fulton Schools of Engineering at Arizona State University, is exploring how to uncover the future of cells associated with Alzheimer’s disease.

The Brafman Lab is looking at various genetic risk factors that have been shown to either increase or decrease the risk of developing Alzheimer’s disease.

“Our research focuses on need,” says Brafman. "The variety of genes associated in Alzheimer’s disease aren’t well known, but understanding them will help explain how someone accumulates risk for developing the disease.”

“When I was growing up, my grandma always believed that I could do something great. Sometimes I try to imagine what it would be like if she completely forgot me,” says Albert Essuman, a research technician in the Brafman Lab, who says he thinks about his own family as inspiration to conduct this research. “Imagine a parent working as hard as they can for their children to make a better life, then one day, the children show up and the parents no longer know them. Making any contribution toward the prevention of Alzheimer’s disease is great and necessary work. This is a terrible disease.”

Advances in cell biology tools

A genetic mutation that accelerates the effects of aging is one factor that can increase the risk of developing Alzheimer’s disease. The mutation makes brain cells more susceptible to damage. Meanwhile, other mutations that decrease the risk of Alzheimer’s can promote cell repair and protect the central nervous system.

Researchers in Brafman’s lab are observing the expression of these gene factors to understand their influence on brain health. One way they are doing this is by directing stem cells to develop into brain cells that contain the mutation of interest. The team then observes how the cells deviate from the known normal process.

To help find the stem cells with correctly edited mutations, the team — which includes Xiao Wang, an associate professor of biomedical engineering in the Fulton Schools — developed a genetic editing method called TREE, or Transient Reporter in Editing Enrichment. Gene editing isn’t successful with every cell, so TREE causes cells to glow a particular color to indicate which ones accepted the desired change. Instead of searching for a needle in a haystack, the needle glows to announce itself.

After identifying and observing the cells, researchers begin looking for abnormalities. Dementia-related diseases are usually impacted by the buildup of damaging proteins where they are normally not found. This creates a traffic jam that prevents communication to cells further down the line, ultimately leading to loss of brain function from neuron death and decreased brain volume. Brafman’s team hopes to improve understanding of how genes can prevent these obstacles.

Recognition for Alzheimer’s disease research

Brafman’s work in studying genetic factors relating to Alzheimer’s disease has been recognized by organizations such as the Alzheimer’s Association and the National Institute on Aging at the National Institutes of Health. These institutions have awarded Brafman more than $1.8 million in funding to investigate five genes that show potential to unravel some of the mechanisms behind how Alzheimer’s develops in the central nervous system.

The Alzheimer’s Association awarded Brafman the 2022 Alzheimer’s Disease Strategic Fund and a 2021 research grant to investigate the activity of the genes known as APOE2 and ABCA7.

"When I was growing up, my grandma always believed that I could do something great. Sometimes I try to imagine what it would be like if she completely forgot me. Imagine a parent working as hard as they can for their children to make a better life, then one day, the children show up and the parents no longer know them. Making any contribution toward the prevention of Alzheimer’s disease is great and necessary work. This is a terrible disease."

–Albert Essuman, research technician in the Brafman Lab

APOE2 is known for its protective influence on brain volume, though little is understood about how the gene governs the immune system within the brain. ABCA7 is a gene predominantly found in people of African descent that may increase the risk of Alzheimer’s by promoting the production of harmful proteins.

The National Institutes of Health is supporting the lab’s research on the influence of age-related genetic mutations in the APOECh, Klotho and BIN1 genes.

APOECh is a rare variant of a gene heavily associated with Alzheimer’s that could help protect the brain from familial Alzheimer’s disease progression. The Klotho gene has a variation that can reduce the risk of disease onset and age-related progression by protecting brain volume.

On the opposite side of the spectrum, Brafman is studying BIN1 for its association with an increased abundance of hazardous proteins.

Influencing education

In addition to pursuing the gene influences of Alzheimer’s disease, Brafman has fully embraced the university’s mission to increase academic accessibility. With the rising interest in online education, Brafman has been working with Fulton Schools leaders to develop the online curriculum to increase students’ access to education.

“I’m very interested in pursuing science but also education and workforce development,” Brafman says. “That’s where I see the next big thing — thinking about how we teach.”

Gayathri Srinivasan, a biomedical engineering doctoral candidate in Brafman’s lab, assists in exploring how genes alter the immune system’s ability to protect the central nervous system. She helps implement genetic changes in immune cells like microglia and astrocytes, known for their ability to manage waste disposal and cell stability. Through this work, Srinivasan is able to observe the mechanisms that cause dementia-related symptoms.

Srinivasan notes that despite her background focusing on the technological side, she was drawn to developmental biology due to the university’s engaging environment and challenging work.

“It’s wonderful to look at these cells and be able to use this tool to see such beautiful structures,” Srinivasan says.

Brafman says it’s important for educators and researchers to reevaluate their endeavors for representation, inclusivity and accessibility. By pursuing research into risk factors specific to underserved communities, they can provide a greater overall understanding of the disease. Encouraging students from diverse backgrounds to get involved in biomedical engineering will open doors to elevate new perspectives.

“I believe this generation in particular is very resilient to the ups and downs of research,” Brafman says. “In addition, this generation is much more technologically savvy, which provides new opportunities.”

As Brafman continues his research to understand the relationship between genetics and brain health, he hopes to build on the known processes behind neurodegeneration and improve treatments.