A recent study, published in the journal PLOS Biology, has revealed that a reduction in mRNA methylation can alleviate the symptoms of Alzheimer’s disease in mice. Blocking this post-transcriptional modification led to an increase in immune cell migration to the brain, and a subsequent decrease in the amount of disease-associated amyloid beta plaques.
Immune cells “eat” amyloid beta
Alzheimer’s disease is one of the most common neurodegenerative disorders. However, despite its prevalence, the exact mechanisms underpinning the disease remain unclear, and there are very few effective treatment options. A common feature of the condition is a build-up of amyloid beta in the brain. This excess protein subsequently forms plaques and disrupts cellular functions. As such, methods to reduce this build-up are commonly explored as potential treatments.
Amyloid beta can be consumed by immune cells known as macrophages. These cells are derived from myeloid cells in the blood, maturing after crossing the blood-brain barrier. The mechanisms underpinning myeloid migration are not fully understood, although post-transcriptional modification of myeloid mRNA is thought to play a role.
The researchers from Shaanxi, China, chose to investigate the role of mRNA methylation in myeloid cells, and its impact on cognitive function in mouse models of Alzheimer’s disease.
A complex pathway
The most common mRNA modification is a form of methylation known as N6-methyladenosine (m6A). The m6A methyltransferase complex consists of a variety of different proteins and has been previously implicated in the onset of neurodegenerative disease. In particular, this modification has been seen to impact cognitive function in mice. To test whether a reduction in m6A methylation could rescue the Alzheimer’s phenotype in a mouse model, the team chose to knockdown expression of a crucial m6A methyltransferase, METTL3, in myeloid cells.
The experiment showed that in the absence of METTL3, the mice had noticeably improved cognitive function. To understand why this was the case, they investigated the pathway affected by METTL3 knockdown. It was observed that METTL3 ablation had a knock-on effect on the expression a variety of genes, including DNA methyltransferase 3A. In the absence of m6A methylation, this gene could not be translated into protein, and could not therefore fulfil its role of binding to the alpha tubulin acetyltransferase 1 (ATAT1) gene. ATAT1 is responsible for the acetylation of tubulin, a cellular component that has also been strongly linked to the onset of neurodegenerative disease.
The researchers observed that a reduction of ATAT1 acetylation of tubulin in response to knockdown of METTL3 led to increased migration of myeloid cells across the blood-brain barrier. These cells then matured into macrophages that destroyed amyloid beta plaques, explaining the restored cognitive function seen previously.
New targets
Alzheimer’s disease and other neurological conditions can be devastating, made more difficult by a lack of effective treatment. The work shown here highlights the complexity of the disease pathology, but also provides hope for potential new treatments. The authors stated that the “results suggest that m6A modifications are potential targets for the treatment of Alzheimer’s disease.” Alongside the identification of this new target, the study also highlights the effectiveness of the immune response to excess amounts of amyloid beta.
