Modifying Messenger RNA May Provide a New Target for Alzheimer’s Disease

Summary: Targeting and reducing methylation of a key mRNA promoted macrophage migration into the brain and may improve cognitive symptoms of Alzheimer’s disease.

Source: PLOS

Reducing the methylation of a key messenger RNA can promote the migration of macrophages into the brain and improve symptoms of Alzheimer’s disease in a mouse model, according to a new study published March 7 in the open-access journal PLOS Biology by Rui Zhang of the Air Force Medical University. in Xian, Shaanxi, China.

The results illuminate a pathway for peripheral immune cells to enter the brain and may provide a new target for the treatment of Alzheimer’s disease.

A putative trigger for the development of Alzheimer’s disease is the accumulation of extracellular amyloid-beta protein plaques in the brain. High levels of amyloid-beta in mice lead to neurodegeneration and cognitive symptoms reminiscent of human Alzheimer’s disease, and reducing amyloid-beta is a key goal in developing new treatments.

One possible pathway to get rid of amyloid-beta is the migration of blood-derived myeloid cells into the brain and their maturation into macrophages, which, along with resident microglia, can consume amyloid-beta. This migration is a complex phenomenon controlled by multiple interacting players, but one potentially important phenomenon is messenger RNA methylation within myeloid cells.

The most common type of mRNA methylation, called m6A, is carried out by the enzyme METTL3, so the authors first asked whether the absence of METTL3 in myeloid cells had any effect on cognition in a 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 prevented when they blocked the migration of myeloid cells into the brain.

How did decreased mRNA methylation promote myeloid cell migration? The authors explained a complex mechanism. Through analysis of mRNA expression patterns and other techniques, they showed that depletion of METTL3 reduced the activity of a master reader protein m6A, which recognizes mRNAs modified by m6A and promotes their translation into protein.

High levels of amyloid-beta in mice lead to neurodegeneration and cognitive symptoms reminiscent of human Alzheimer’s disease, and reducing amyloid-beta is a key goal in developing new treatments. The image is in the public domain

This led to a decrease in another protein and that inhibited the production of another protein, called ATAT1. Loss of ATAT1 reduced the binding 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 amyloid-beta, 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. Because mRNA methylation has a fundamental effect on a wide variety of downstream targets, effective drug development within this pathway may require further downstream movement to avoid unwanted 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), Program for Ph.D. Research funding was initiated by Xinxiang Medical University grant 505249 to YHL, and National Key Research and Development Program grant 2016YFC1303200 to ZR. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

About this Alzheimer’s disease genetics and research news

Author: Claire Turner
Source: PLOS
Contact: Claire Turner – PLOS
Image: Image is in the public domain

Original Research: Open Access.
“Loss of the m6A methyltransferase METTL3 in monocyte-derived macrophages ameliorates Alzheimer’s disease pathology in mice” by Rui Zhang et al. PLOS Biology

ABSTRACT

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Loss of the m6A methyltransferase METTL3 in monocyte-derived macrophages ameliorates Alzheimer’s disease pathology in mice

Alzheimer’s disease (AD) is a heterogeneous disease with complex clinicopathological 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 3 (METTL3) deficiency in monocyte-derived macrophages improved cognitive function in an amyloid beta (Aβ)-induced AD mouse model.

Mechanistic study showed that METTL3 ablation attenuated m6A modification in DNA methyltransferase 3A (Dnmt3a) mRNAs and consequently impaired YTH N6-methyladenosine RNA protein 1 (YTHDF1)-mediated translation of DNMT3A.

We identified that DNMT3A bound to the promoter region of alpha-tubulin acetyltransferase 1 (Atat1) and maintained its expression. Depletion of METTL3 resulted in down-regulation of ATAT1, reduced α-tubulin acetylation, and subsequently increased monocyte-derived macrophage migration and Aβ clearance, which led to amelioration of AD symptoms.

Collectively, our findings indicate that m6A methylation may be a promising target for the treatment of AD in the future.