Summary: Targeting and reducing methylation of a key mRNA promoted macrophage migration in the brain and may improve cognitive symptoms of Alzheimer’s disease.
Reducing methylation of a key messenger RNA may promote migration of macrophages in the brain and improve symptoms of Alzheimer’s disease in a mouse model, according to a new study published on March 7e in the open access journal PLOS Biology by Rui Zhang of Air Force Medical University in Xian, Shaanxi, China.
The results shed light on a pathway for peripheral immune cells to enter the brain and could provide a new target for the treatment of Alzheimer’s disease.
A suspected trigger for the development of Alzheimer’s disease is the accumulation of extracellular amyloid-beta protein plaques in the brain. Elevated levels of beta-amyloid in mice lead to neurodegeneration and cognitive symptoms reminiscent of human Alzheimer’s disease, and reducing beta-amyloid is a major goal in the development of new treatments.
One potential pathway to get rid of beta-amyloid is the migration of blood-derived myeloid cells into the brain and their maturation into macrophages, which, along with resident microglia, can consume beta-amyloid. This migration is a complex phenomenon controlled by multiple interacting actors, but a potentially important phenomenon is messenger RNA methylation in myeloid cells.
The most common type of mRNA methylation, called m6A, is performed by the enzyme METTL3. The authors therefore first asked whether METTL3 deficiency in myeloid cells had an effect on cognition in the mouse model of Alzheimer’s disease. They found that it did – the treated mice performed better on various cognitive tests, an effect that could be inhibited when they blocked the migration of myeloid cells into the brain.
How did decreasing mRNA methylation promote myeloid cell migration? The authors elucidated a complex mechanism. Through analysis of mRNA expression patterns and other techniques, they showed that depletion of METTL3 reduced the activity of a key m6A-reading protein, which recognizes mRNAs modified by m6A and promotes their translation into protein.
This led to a decrease in another protein, and it inhibited the production of another protein, called ATAT1. Loss of ATAT1 reduced the attachment of acetyl groups to microtubules, and this reduction in turn promoted the migration of myeloid cells into the brain, followed by maturation into macrophages, increased clearance of beta- amyloid 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. Since mRNA methylation has a fundamental effect on a wide variety of downstream targets, effective drug development in this pathway may require moving further downstream to avoid adverse effects.
Funding: This study was supported by grants from the National Natural Science Foundation of China (31801128 to YHL, 81630069, 31771439 to YA, 82173046 to ZR, 82173162 to ZX), the PhD program. The seed research funding from Xinxiang Medical University grants 505249 to YHL, and the national key research and development program grants 2016YFC1303200 to ZR. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
About this genetics and Alzheimer’s disease research news
Author: Claire Turner
Contact: Claire Turner – PLOS
Picture: Image is in public domain
Original research: Free access.
“Loss of m6A methyltransferase METTL3 in monocyte-derived macrophages ameliorates Alzheimer’s disease pathology in mice” by Rui Zhang et al. PLOS Biology
Loss of m6A methyltransferase METTL3 in monocyte-derived macrophages improves Alzheimer’s disease pathology in mice
Alzheimer’s disease (AD) is a heterogeneous disease with complex clinicopathologic features. To date, the role of m6A RNA methylation in monocyte-derived macrophages involved in AD progression is unknown.
In our study, we found that methyltransferase type 3 (METTL3) deficiency in monocyte-derived macrophages improved cognitive function in an amyloid-beta (Aβ)-induced AD mouse model.
The mechanistic study showed that the ablation of METTL3 attenuated the m6A modification of DNA methyltransferase 3A (dnmt3a) mRNA and consequently altered the YTH N6-methyladenosine 1 (YTHDF1) RNA-binding protein-mediated translation of DNMT3A.
We identified that DNMT3A binds to the promoter region of alpha-tubulin acetyltransferase 1 (Atat1) and maintained its expression. METTL3 depletion resulted in downregulation of ATAT1, reduced α-tubulin acetylation and subsequently increased migration of monocyte-derived macrophages and Aβ clearance, which which resulted in an alleviation of the symptoms of Alzheimer’s disease.
Together, our results demonstrate that m6A methylation could be a promising target for the treatment of AD in the future.