Could modified mRNA therapy help treat Alzheimer’s disease?

RNA (ribonucleic acid) is a molecule that can be found in all living cells. The main job of RNA is to carry protein-making instructions from the DNA to the areas of the cell where proteins are made. Messenger RNA, or mRNA, is a specific type of RNA.

Recently, mRNA has received a lot of interest as scientists have used it to create vaccines, most notably COVID-19 vaccines.

And researchers have been looking at using modified mRNA to treat diseases including cystic fibrosis, heart disease, and certain cancers, including colon cancer.

In this study, researchers decided to look for a way to lower the amount of beta-amyloid protein in the brain, which many believe is one of the causes of Alzheimer’s disease.

Scientists knew that one way to do this was to move more myeloid cells into the brain. Myeloid cells can turn into macrophages, which help remove beta-amyloid protein accumulations in the brain.

This movement of myeloid cells into the brain is partially regulated by a specific chemical reaction known as methylation occurring in its mRNA.

The most common type of mRNA methylation is known as m6A, and occurs through an enzyme called METTL3.

Scientists found that lowering amounts of METTL3 in a mouse model improved cognition. They also found that decreased mRNA methylation helped move more myeloid cells into the brain.

“The loss of m6A modification on mRNA of [the] DNMT3A gene inhibited its protein expression,” Dr. Rui Zhang of the Air Force Medical University, lead author of this study, explained to Medical News Today. “Consequently, it led to downregulation of alpha-tubulin acetyltransferase 1 (ATAT1).”

“ATAT1 is a bad guy to block [the] migration of macrophage. Inhibition of ATAT1 enhanced migration of monocyte-derived macrophages and [beta-amyloid] clearance, which led to the alleviated symptoms of Alzheimer’s disease,” Dr. Zhang explained.

When ATAT1 was lowered, researchers reported that myeloid cells were able to enter the brain, turn into macrophages, clear out amyloid-beta protein, and improve cognition in mice.

Dr. Zhang said the goal of this study was to study the function and mechanism of m6A modification of mRNA in the macrophage, especially in Alzheimer’s disease.

“We [never] realized the loss of m6A can have such a potential effect on the attenuation of Alzheimer’s disease status, but it really happens here. Our study pinpoints the potential therapeutic effect of macrophages with the loss of RNA m6A modification in the Alzheimer’s disease mouse model. If we can use a pharmacological strategy to inhibit RNA m6A modification in macrophages, it may improve the life quality of Alzheimer’s disease patients.”

– Dr. Rui Zhang

As for the next step in this research, Dr. Zhang said the team is “planning to screen and identify the m6A modification inhibitors and try to [deliver them] into the macrophage (microglia).”

MNT also spoke with Dr. Santosh Kesari, a neurologist at Providence Saint John’s Health Center in Santa Monica, CA, and regional medical director for the Research Clinical Institute of Providence Southern California, about this study. Dr. Kesari was not involved in this research.

In his opinion, he told us, this was a very interesting potential mechanism in the treatment of Alzheimer’s disease.

“The study basically showed that […] reducing the levels of METTL3 protein increases the infiltration of immune cells from the blood into the brain to clear out the amyloid plaque that gets built up and causes the damage that we see in dementia patients,” Dr. Kesari explained.

“This is the starting point of opening up a new biology for Alzheimer’s, and validates that the immune system has a great role in neurodegenerative diseases that we don’t quite understand,” he said.

Dr. Kesari added this is the start of a variety of studies that need to be done to validate these findings and understand the mechanisms more clearly so they can be translated into humans in the future.

“Part of that really relates to potentially developing a drug that can do the same thing that the authors did in the study genetically,” he concluded.