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N6-methyladenosine participates in mouse hippocampus neurodegeneration via PD-1/PD-L1 pathway
Wen Hu1, Hongbo Xie2, Yubing Zeng3
1Department of Otolaryngology-Head and Neck Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China.
Abstract:
Developmental abnormalities and hippocampal aging leads to alteration in cognition. In the brain, N6-methyladenosine (m6A) is a common and reversible mRNA alteration that is essential for both neurodevelopment and neurodegeneration. However, its function in the postnatal hippocampus and the specific mechanisms regulating hippocampus-related neurodegeneration still awaits elucidate. We identified dynamic m6A modifications in postnatal hippocampus at different stages (at 10 days postnatally, and at 11 and 64 weeks of age). m6A shows a definite cell-specific methylation profile and m6A modification displays temporal dynamic during neurodevelopment and aging. Differentially methylated transcripts in the aged (64-week-old) hippocampus were enriched in microglia. The PD-1/PD-L1 pathways was identified that may participate in the cognitive dysfunction associated with an aged hippocampus. Furthermore, Mettl3 was spatiotemporally expressed in the postnatal hippocampus, which was highly expressed at the age of 11 weeks compared with the other two timepoints. Ectopic expression of METTL3 in mice hippocampus mediated by lentiviral infection resulted in high expression of genes related to PD-1/PD-L1 pathway and significant spatial cognitive deficit. Together, our data show that m6A dysregulation, which is mediated by METTL3, most likely contributes to cognitive deficits linked to the hippocampus via the PD-1/PD-L1 pathway.
Insights
N6-methyladenosine (m6A) RNA modifications, regulated by METTL3, are crucial for hippocampal function. Dysregulation of m6A contributes to cognitive deficits in aging via the PD-1/PD-L1 pathway.
Area of Science:
- Neuroscience
- Epigenetics
- Molecular Biology
Background:
- N6-methyladenosine (m6A) is a key mRNA modification vital for neurodevelopment and neurodegeneration.
- The role of m6A in the postnatal hippocampus and its link to neurodegeneration requires further investigation.
Purpose of the Study:
- To investigate the dynamic changes and cell-specific profiles of m6A modifications in the developing and aging hippocampus.
- To elucidate the mechanisms by which m6A dysregulation contributes to age-related cognitive decline.
Main Methods:
- Analysis of m6A modifications in mouse hippocampi at different postnatal ages (10 days, 11 weeks, 64 weeks).
- Identification of differentially methylated transcripts in aged hippocampus.
- Investigation of the PD-1/PD-L1 pathway and METTL3 expression.
- Lentiviral-mediated ectopic expression of METTL3 in mouse hippocampus to assess cognitive function.
Main Results:
- Dynamic and cell-specific m6A modification patterns were observed during hippocampal development and aging.
- Aged hippocampus showed enrichment of differentially methylated transcripts in microglia.
- METTL3 expression peaked at 11 weeks and its ectopic expression in the hippocampus led to upregulation of PD-1/PD-L1 pathway genes and spatial cognitive deficits.
Conclusions:
- m6A RNA modifications, regulated by METTL3, play a significant role in hippocampal function.
- METTL3-mediated m6A dysregulation contributes to cognitive impairment in aging hippocampus, potentially through the PD-1/PD-L1 pathway.
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