How do researchers at a children’s hospital make a discovery about Alzheimer’s disease, a disorder associated with aging? By following the science.
Led by Douglas Green, PhD, St. Jude Department of Immunology chair, a group of scientists were investigating how the immune system responds to cancer. They were studying autophagy, a process where a cell consumes pieces of itself to recycle nutrients and clear away damaged or unneeded parts. It’s a cell’s way of cleaning up.
Several proteins are involved in autophagy. To find out whether autophagy might play a role in immune response, the researchers focused on the LC3 protein in microglial cells. These cells are the primary immune cells of the brain and central nervous system.
That’s when science threw them a curve ball. The researchers made a discovery—one with implications for cancer immunotherapy, but also for Alzheimer’s disease.
“You can expect your research to take you in one direction, but then the science pulls you in another,” Green says. “Following where the results lead can bring forward some truly fascinating discoveries.”
Alzheimer's and LC3
The researchers discovered that LC3 helps microglial cells move proteins through their membrane in a process called endocytosis. LC3-associated endocytosis, or LANDO, enables microglial cells to clear away beta-amyloid protein. A buildup of this protein is one of the factors underlying the establishment and progression of Alzheimer’s disease.
Imagine a car wash. Receptors on the surface of microglial cells bind to beta-amyloid proteins like cars hook into the track of an automatic carwash. The cars bring with them dirt and debris that gets cleared away in the wash, much like beta-amyloid that is consumed by microglial cells. When the beta-amyloid is disposed of, the receptors return to the microglial cell surface like glistening cars returning to the road.
A car wash needs hardware to attach the car to the track. Similarly, LANDO requires several proteins to help it do its job. The proteins, called Rubicon, Beclin1, ATG5 and ATG7, decline with age as their expression decreases. This explains how in older individuals LANDO can start to lag behind, unable to clear the beta-amyloid protein.
The researchers realized what they had found. Activating LANDO appears to offer protection against neurodegenerative disease, guarding against toxic neuroinflammation and neurodegeneration, including memory problems.
“Turning on LANDO in microglial cells could form the basis of a new type of therapy, where cells are able to increase their ability to clear away beta-amyloid, reducing neuroinflammation,” explains Bradlee Heckmann, PhD, a postdoctoral fellow in Green’s lab.
Although the link between Alzheimer’s disease, beta-amyloid proteins and LANDO is clear, the pathway is still relevant for research into how the immune system responds to cancer. Inhibiting LANDO could also help boost the effectiveness of cancer immunotherapies.
“At St. Jude we care deeply about the health of children, and we still care about them even when they get much older,” Green says. “We think that our discoveries on Alzheimer’s disease will bring us back to insights into pediatric brain cancers. Following the science is the St. Jude way. We never know where discoveries will lead us.”
Naming a Discovery
In biology, discovering something new often means you get to name it. Green and Heckmann named their find LC3-associated endocytosis, but they wanted an acronym that might resonate more with scientists and the public.
Talking it over with their colleagues one evening, the researchers found their conversation flitting back and forth between their work in the lab and the latest movie in the Star Wars saga.
As the conversation flowed, Green mentioned the character Lando Calrissian, who is a smuggler and pilot in the films. Eventually it clicked for Green, and LC3-associated endocytosis became LANDO.
What convinced Heckmann that the acronym was fitting were the images of LANDO at work in microglial cells.
“The image of red-stained beta-amyloid protein and microglial cells stained green against a black background looked like something from Star Wars,” he says.
From Promise, Winter 2020