Aging-US: N6-methyladenosine and its clinical relevance in cognitive dysfunctions09-21-2021
Aging-US published "N6-methyladenosine (m6A) modification and its clinical relevance in cognitive dysfunctions" which reported that the authors systematically investigated the molecular alterations of m6A regulators and their clinical relevance with cognitive dysfunctions using published datasets of Alzheimer's Disease, vascular dementia, and mild cognitive impairment.
The expressions of m6A regulators vary in different tissues and closely correlate with neurodegenerative pathways. They identified co-expressive m6A regulators SNRPG and SNRPD2 as potential biomarkers to predict transformation from MCI to AD. Collectively, these findings suggest that m6A methylations as potential biomarkers and therapeutic targets for cognitive dysfunction.
The cerebrospinal fluid concentrations of phosphorylated Tau 181 and amyloid-beta 42 are considered biomarkers for AD. There are no diagnostic or therapeutic biomarkers for VD. Mild cognitive impairment is a transitional and reversible stage that can diverge to normal aging and neurocognitive disorder. MCI increases the risk of developing neurocognitive disorders, but the trajectory of individuals varies. N6-methyladenosine is the most common RNA modification in eukaryotic cells. The abundance of m6A in the brain gradually increases with age and peaks in adulthood. M6A is highly enriched in adult brain tissue and plays a critical role in neurogenesis, neurodevelopment, and neurological disorders. M6A modification on messenger RNA affects the proliferation and differentiation of neural progenitor cells, and elucidating dysregulations and alterations of m6A perturbations facilitates a comprehensive understanding of RNA methylation-based stem cell or gene-targeted diagnosis and therapy.
Dysregulations of m6A have been associated with the perturbations of cell proliferation and cell death in different diseases.
Alternations of RNA methylation modified genes in the central nervous system. Little evidence has elucidated the relationships between m6A regulators and neurodegeneration, such as dementia. A recent study by Han et al. using APP/PS1 transgenic mice indicated that m6A abnormality is closely related to AD.
Figure 7. Expression differences on m6A-related regulators between APOE ɛ4+ and APOE ɛ4− groups. (A–E) Five representative DEGs between two groups. *p < 0.05, **p < 0.01, ***p < 0.001.
The Jiang/Bi Research Team concluded in their Aging-US Research Output that the 4 allele of APOE is the most common and influential genetic risk factor for developing AD. Similarly, they found a significant increase in most m6A-related regulators within the AD APOE ɛ4+ group, suggesting a complex regulation of epigenetic alterations between the ɛ4 allele and AD. The authors further figured out that FTO's effect on dementia or AD risk mainly was through interaction with the APOE ɛ4 allele. We did not find the difference of FTO expression between APOE ɛ4+/− groups, suggesting that we adopted different samples.
Consistent with Han's study reporting an elevated level of METTL3 in AD mice, these authors found that the AD APOE ɛ4 + group has a higher expression of METTL3. Ectopic expression of RBMX was reported to decrease the APOE receptor’s splicing and was critical to cholesterol homeostasis and, possibly, AD development.
Full Text - https://www.aging-us.com/article/203457/text
Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research as well as topics beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, cancer, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR among others), and approaches to modulating these signaling pathways.