Alzheimer’s disease is a progressive neurological disorder that affects a person’s memory, thinking, and behavior. It is the most common cause of dementia, which is a decline in cognitive function severe enough to interfere with daily activities.
Reducing the methylation of a key messenger RNA can promote migration of macrophages into the brain and ameliorate symptoms of Alzheimer’s disease in a mouse model, according to a new study publishing March 7, 2023 in the open access journal PLOS Biology by Rui Zhang of Air Force Medical University in Xian, Shaanxi, China.
The findings reveal one route by which peripheral immune cells enter the brain and could suggest a new avenue for Alzheimer’s disease treatment. There is currently no cure for Alzheimer’s disease, but there are treatments that can help manage symptoms and improve quality of life. These include medications that can temporarily improve memory and cognitive function, as well as non-pharmacological approaches such as cognitive and behavioral therapies.
Amyloid-beta plaque buildup in the brain is thought to be a cause of Alzheimer’s disease. These plaques are protein-rich and extracellular. Reducing amyloid-beta is a key objective in the development of new therapeutics since it causes neurodegeneration and cognitive symptoms in mice that are similar to those of human Alzheimer’s disease.
Our results suggest that m6A modifications are potential targets for the treatment of Alzheimer’s disease.
The authors
The movement of blood-derived myeloid cells into the brain and their development into macrophages, which, along with local microglia, can devour amyloid-beta, represent one possible route for amyloid-beta removal.
The methylation of messenger RNA within the myeloid cells may be a significant participant in the complicated phenomena of migration, which is regulated by several interdependent players.
The most common type of mRNA methylation, called m6A, is carried out by the enzyme METTL3, so the authors first asked whether deficiency of METTL3 in myeloid cells had any effect on cognition in the Alzheimer’s disease mouse model. When they stopped the migration of myeloid cells into the brain, they discovered that treated mice scored better on a variety of cognitive tests.
How did decreased mRNA methylation promote myeloid cell migration? The authors elucidated a complex mechanism. They demonstrated that METTL3 depletion decreased the activity of a crucial m6A reader protein, which detects m6A-modified mRNAs and facilitates their translation into protein. They did this by analyzing mRNA expression patterns and using other methods.
That led to a decline in another protein, and that inhibited the production of yet another protein, called ATAT1. Deletion of ATAT1 resulted in decreased acetyl group attachment to microtubules, which in turn aided in myeloid cell migration into the brain, maturation into macrophages, higher amyloid-beta clearance, and improved cognition in mice.
“Our results suggest that m6A modifications are potential targets for the treatment of Alzheimer’s disease,” the authors concluded, while noting that much about this pathway in Alzheimer’s disease remains to be explored.
Effective medication development within this route may involve pushing further downstream to prevent side effects because mRNA methylation has a fundamental impact on a wide range of downstream targets.
