A type of brain cell that plays a vital role in maintaining neural networks and repairing injuries lies at the core of a promising newly published Nature study on Alzheimer's disease from the USF Health Byrd Alzheimer's Center and Research Institute.
These cells are called microglia. To understand how they function, picture the vintage '80s video game Pac-Man and the iconic character gobbling up everything in its maze-like path. In this case, however, it's not tiny ghosts being devoured, but harmful proteins.
"Microglia are immune cells in the brain and they are scavengers," said Gopal Thinakaran, PhD, CEO and endowed chair of the Byrd Institute. "They play an important role in clearing up debris in the brain. And they also have a very important role in Alzheimer's disease."
Microglia multiply as needed - think millions of Pac-Men and Ms. Pac-Men roaming neural pathways - to keep the brain debris-free.
"Imagine the brain as a bustling city, full of nerve cells or neurons, sending important messages back and forth," Dr. Thinakaran said. "Microglia are like the city's sanitation crew, emergency responders and even urban planners, all rolled into one. These tiny cells, making up about 10 percent of the brain, are incredibly important for keeping the city running smoothly and adapting to change."
Microglia are constantly sending out feelers or projections to monitor the brain's environment, searching for any signs of trouble, like infection, damage, or unwanted debris. And when they find it, they transform from their resting state to an active blob-like shape and engulf, in classic video-game style, harmful substances.
However, in aging individuals with diseased brains, microglia have a more difficult time keeping up with the garbage removal. Eventually, they succumb to the chronic pathology that permeates the brain, ultimately becoming sluggish and swollen, laden with oily lipids, and unable to remove fatty deposits of lipids efficiently.
The factors that cause microglia to lose their effectiveness are part of the new study published Sept. 3 in the prestigious journal Nature, with Dr. Thinakaran serving as the co-senior author of an investigation done in collaboration with his former colleague Jubao Duan, PhD, at the University of Chicago and Endeavor Health Research Institute.
The paper shows how a variation in a particular gene, called PICALM, has a profound effect on the microglia. This change in the gene disrupts the microglia, heightening the likelihood of Alzheimer's developing, explained Ari Sudwarts, PhD, co-first author on the paper and a postdoctoral research scholar in the Morsani College of Medicine.
"We made significant progress in understanding the functions of PICALM - the third-most significant risk gene for late-onset Alzheimer's disease," Dr. Sudwarts said. "We found that a variant of PICALM affected the immune cells of the brain, reducing their ability to clear debris, and causing a buildup of cholesterol and lipids. Understanding the functions disrupted by a specific risk gene gives new targets for developing pharmaceuticals for patients who have this genetic variant."
Dr. Thinakaran is working to learn more about PICALM and other common genetic variants that also have a profound impact, increasing the risk of developing the disease.
"This is like gene mutations that cause cancer," he said. "If you have such a mutation, you're going to pass it on to your kids. There are only about three genes that have that kind of capability for Alzheimer's disease. All the others are called risk factors - they don't cause the disease in all people, but they increase one's lifetime risk."
He is fascinated by the challenge of figuring out how gene variants affect the disease, as well as how scientists can separate genetic effects from the lifestyle factors known to affect Alzheimer's risk.
"An individual's risk in a lifetime becomes different, whether you exercise or not, whether you keep an active lifestyle or you're highly educated and many other things," Dr. Thinakaran said. "So it becomes really difficult to narrow down and study genetic impacts."
But over the last two decades, genetic methods have become more advanced and zeroed in on "hotspots" in genes that increase one's lifetime risk. One such hotspot is the PICALM gene, which is associated with a risk of developing late-onset Alzheimer's.
Much research has focused on the PICALM gene, as well as the PICALM protein it produces, over the past two decades, including that done at the University of Chicago and Endeavor Health Research Institute by Dr. Duan. Dr. Thinakaran collaborated with Dr. Duan on a research grant to further study PICALM-related risk factors and received federal funding in 2019, just after Dr. Thinakaran moved to USF.
They oversaw a dual-lab study, involving cultured human-derived brain cells in petri dishes. Over time, this allowed them to gain a greater understanding of molecular changes in PICALM and the resulting increased risk of developing Alzheimer's. They learned that 30 percent of the population has a certain variant, or allele, of the PICALM gene. Called the "minor allele" of PICALM, it appears to protect people against Alzheimer's. But they wanted to understand the reason - the mechanism - for that.
When they examined the data in cultured cells, they found the answer lay in the Pac-Men of the brain - the microglia.
"Dr. Duan found that the risk allele in PICALM only showed up in microglia," Dr. Thinakaran stated. "So we said, let's introduce the change in the microglia, adding both the minor allele, which is protected from risk, and the major allele, which is not."
As a result, they were able to find that the major allele reduces PICALM protein levels in the microglia. Having less PICALM protein damages organelles - functional structures within a cell - that degrade waste proteins called lysosomes. The less effective organelles disturb how proteins and lipids are managed in the cell, ultimately reducing the capacity for microglia to engulf protein material like amyloid and tau in the brain.
"This creates these compact structures called lipid droplets that cause further havoc in a cell, and it impedes the microglia from doing its job," said Dr. Thinakaran. "It's extremely rare to have a story develop like this, and it took five years to unfold."
The take-away message?
"Many risks are being identified in microglia," he said. "And we are giving kind of a roadmap for one risk, and how the process results in lipid dysregulation and how the further accumulation of lipid droplets really starts to make the microglia ineffective. The knowledge we have gained adds one more piece to the Alzheimer's puzzle we are putting together."
