Researchers have uncovered yet another potential treatment mechanism in the quest to find new therapies for Alzheimer’s disease.
In an article published March 7 in PLOS Biology, scientists from China’s Air Force Medical University described how they created a mouse model of Alzheimer’s with a gene change that ultimately led myeloid cells to infiltrate the brain, where they matured into immune cells called macrophages—which then consumed the disease’s characteristic amyloid-beta plaques. This improved cognition in the mice compared to genetically normal Alzheimer’s models.
Some clinical trials are investigating amyloid-beta targeting drugs for early Alzheimer’s, the researchers wrote in their paper, adding “our results may supply a new choice for treatment strategies.”
The gene at the heart of the study encodes the enzyme METTL3. METTL3 is an RNA N6-methyladenosine, or m6A, methyltransferase. It regulates gene expression by performing what’s known as m6A methylation on many different types of RNA, including mRNA. While previous research showed that normal METTL3 function plays a key role in long-term memory consolidation in the hippocampus, another study published in 2020 showed that it was expressed at higher levels in mouse models of Alzheimer’s compared to controls. This suggested that m6A methylation of RNA might be playing a role in the disease.
To find out if that was the case, the researchers developed a mouse model without the gene for METTL3 in myeloid cells, which are cells derived from bone marrow that go on to form different types of blood and immune cells. The team focused on myeloid cells specifically because recent research has shown that the cells can cross the blood-brain barrier and differentiate into macrophages, according to the paper. These so-called “blood-derived macrophages” are thought to work with the brain’s resident immune cells, microglia, on a variety of processes, from neurodegeneration to repairing and protecting the central nervous system from damage.
The researchers then injected amyloid-beta plaques in the brains of their new models and a cohort of unaltered mice to induce Alzheimer’s and put them through a pair of maze tests to assess their cognitive function.
Seeing that the METTL3-deficient group performed better than their counterparts, they replicated their results by transplanting bone marrow from genetically unaltered and METTL3-knockout models into two more groups of mice, inducing Alzheimer’s in all of them and having them perform the same tests. The mice who received bone marrow from the METTL3-knockout mice outperformed the ones who received it from wild-type models. Together, the results suggested that inhibiting METTL3 slowed Alzheimer’s progression, the researchers wrote.
Next, the team took a closer look at what was happening in the METTL3-deficient cells. Based on a previous study showing that a cellular process called microtubule acetylation might play a role in neurodegenerative disease, they compared the microtubules of wild-type macrophages to those without METTL3. The microtubules of METTL3 knockout cells had less acetylation than the ones in wild-type cells, along with lower expression of a key gene involved in the process, ATAT1. But further analyses showed that METTL3 didn’t directly impact ATAT1 expression, which meant the researchers must be missing a puzzle piece.
More analyses of mRNA expression patterns revealed it. They found that under normal conditions, METTL3 regulates the expression of another gene, DNMT3A, through m6A methylation. This is carried out with the help of a reader protein, a type of protein that recognizes and binds to modified DNA or RNA—in this case, one that specifically recognizes mRNAs that have undergone m6A methylation. DMT3A expression increases ATAT1 expression, which leads to microtubule acetylation.
But without METTL3, there wasn’t enough reader protein activity for DMT3A to be expressed—thus inhibiting ATAT1 and microtubule acetylation. Further experiments showed that the lack of microtubule acetylation prompted the myeloid cells to enter the brain, where they matured into macrophages and destroyed the amyloid-beta plaques. This, in turn, improved the models’ cognition.
While the complex mechanism leaves many open questions, it does suggest that targeting m6A methylation could be a route for treating Alzheimer’s disease. Given that mRNA methylation is an important process for gene regulation, future research would need to figure out where along the pathway they could intervene without causing side effects.
The road to treating Alzheimer’s has been paved with failures, though there have been a couple of recent wins. In the few years, the FDA has approved two drugs for early, mild disease. Both are monoclonal antibodies, both were developed by Biogen and Eisai, and neither is without controversy. Aducanumab, trade name Aduhelm, got the FDA green light in June 2021 despite concerns that there wasn’t enough evidence that it worked, while lecanemab, or Leqembi, was approved this past January with still-unanswered questions about its safety.