N6-methyladenosine dynamics in neurodevelopment and aging, and its potential role in Alzheimer’s disease

Abstract

Background N6-methyladenosine (m6A) modification is known to impact many aspects of RNA metabolism, including mRNA stability and translation, and is highly prevalent in the brain. Results We show that m6A modification displays temporal and spatial dynamics during neurodevelopment and aging. Genes that are temporally differentially methylated are more prone to have mRNA expression changes and affect many pathways associated with nervous system development. Furthermore, m6A shows a distinct tissue-specific methylation profile, which is most pronounced in the hypothalamus. Tissue-specific methylation is associated with an increase in mRNA expression and is associated with tissue-specific developmental processes. During the aging process, we observe significantly more m6A sites as age increases, in both mouse and human. We show a high level of overlap between mouse and human; however, humans at both young and old ages consistently show more m6A sites compared to mice. Differential m6A sites are found to be enriched in alternative untranslated regions of genes that affect aging-related pathways. These m6A sites are associated with a strong negative effect on mRNA expression. We also show that many Alzheimer-related transcripts exhibit decreased m6A methylation in a mouse model of Alzheimer’s disease, which is correlated with reduced protein levels. Conclusions Our results suggest that m6A exerts a critical function in both early and late brain development in a spatio-temporal fashion. Furthermore, m6A controls protein levels of key genes involved in Alzheimer’s disease-associated pathways, suggesting that m6A plays an important role in aging and neurodegenerative disease.

m6A Modification in Mammalian Nervous System Development, Functions, Disorders, and Injuries

“…Transcriptome-wide sequencing of human and mouse brains showed that m 6 A modification is spatiotemporally regulated during neurodevelopment and aging ( Shafik et al, 2021 ). Increased m 6 A sites are observed as age increases.…”

“…Increased m 6 A sites are observed as age increases. The dynamically regulated m 6 A sites are enriched in alternatively untranslated regions of genes involved in aging-related pathways ( Shafik et al, 2021 ). Alzheimer’s disease (AD) is the most common form of dementia among elderly people ( Bateman et al, 2012 ).…”

“…Alzheimer’s disease (AD) is the most common form of dementia among elderly people ( Bateman et al, 2012 ). The m 6 A levels of many transcripts involved in AD-associated pathways are decreased in the brain of a familial AD mouse model (5XFAD) ( Shafik et al, 2021 ). In contrast, m 6 A levels are elevated in the cortex and hippocampus of APP/PS1 transgenic mice, another AD mouse model, compared with WT mice ( Han et al, 2020 ).…”

Emerging Role of m6 A Methylome in Brain Development: Implications for Neurological Disorders and Potential Treatment

“…As discussed further, studies in human populations and in mouse models have shown that specific dysregulations in m 6 A mRNA methylation contribute to AD pathogenesis. Typically, m 6 A levels in various brain regions increase with aging, and this disposition was shown to likely have relevance for AD development (Shafik et al, 2021). Interestingly, while METTL3 is downregulated in AD brain (hippocampus), it was observed to have accumulated in the postmortem AD brain at levels comparable to the insoluble Tau protein therein (Huang H. et al, 2020).…”

Erasing m6A-dependent transcription signature of stress-sensitive genes triggers antidepressant actions

“…The formation of m 6 A is catalyzed by a methyltransferase complex (Methyltransferase-like 3, METTL3; methyltransferase-like 14, METTL14 and Wilms tumor 1-associated protein, WTAP) and erased by demethylases, including fat mass- and obesity-associated (FTO) protein and the α-ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5) protein ( Jia et al, 2011 ; Liu et al, 2014 ; Ping et al, 2014 ; Wang et al, 2016 ; Zheng et al, 2013 ). Emerging evidence indicates that aberrant m 6 A may be considered a new layer of epigenetic mechanisms underlying the pathogenesis of psychiatric diseases, such as cocaine addiction ( Hess et al, 2013 ), alcohol use disorder ( Bohnsack et al, 2019 ) and Alzheimer's disease ( Shafik et al, 2021 ). For major depressive disorder (MDD), a recent study demonstrated that the location and time of stress exposure alter m 6 A modifications ( Engel et al, 2018 ).…”