In a recent study, scientists from the St. Jude Children’s Research Hospital discovered LC3-related endocytosis (LANDO) and its role in neuroinflammation. This discovery has deepened researchers’ understanding of potential Alzheimer’s disease treatment. The results have been published in Science Advance.
Researchers have previously discovered the LANDO pathway in microglia (the main immune cells of the brain and central nervous system), and after deleting the genes required for this pathway, the progression of Alzheimer’s disease in a mouse model will accelerate. Therefore, the researchers showed that LANDO can prevent the occurrence of neuroinflammation, which is one of the hallmarks of Alzheimer’s disease.
ATG16L protein is very important in the process of autophagy. In addition, ATG16L can also play a role in LANDO. The researchers found that if the WD domain of ATG16L is deleted, the LANDO process will be inhibited while autophagy continues.
“We learned about this pathway in the context of brain tumor research, but it has major implications for neuroinflammatory and neurodegenerative disease,” said senior author Douglas Green, Ph.D., chair of the St. Jude Immunology Department. “We’ve shown that deficiency in LANDO, combined with aging, can lead to Alzheimer’s disease in a unique mouse model, and there is evidence suggesting that this could also be the case in humans.”
In this study, the researchers used a new mouse model with specific defects in the WD domain of ATG16L. Therefore, the autophagy process of this mouse model can proceed normally, but the LANDO pathway is blocked. By the time the mice were 2 years old, they showed symptoms and pathological features similar to human Alzheimer’s disease.
The researchers also analyzed tissue samples from human Alzheimer’s disease and studied the expression of proteins (including ATG16L) that regulate LANDO. In Alzheimer’s disease patients, the expression of these proteins is reduced by more than 50%. The researchers used a compound that inhibits inflammasome to treat the mouse model. After analyzing the behavior of the model, they found that in addition to reducing neuroinflammation, the model’s cognition and memory were also improved.
1. L. Heckmann el al., “Noncanonical function of an autophagy protein prevents spontaneous Alzheimer’s disease,”Science Advances (2020).