miRNA-126a-3p participates in hippocampal memory via alzheimer's disease-related proteins
Bao Xue1, Yu Qu1, Xia Zhang1,2,3,4,5
1Institute of Neuropsychiatric Diseases, Qingdao University, Qingdao, Shandong 266001, People's Republic of China.
Abstract:
Memory formation and consolidation necessitate gene expression and new protein synthesis. MicroRNAs (miRNAs), a family of small noncoding RNAs that inhibit target gene mRNA expression, are involved in new memory formation. In this study, elevated miR-126a-3p (miR-126) levels were found to contribute to the consolidation of contextual fear memory. Using different commonly mined algorithms and luciferase reporter assay, we found two Alzheimer's disease (AD)-related proteins, namely EFHD2 and BACE1, but not ADAM9, were the targets downregulated by miR-126 after CFC training. Moreover, we indicated that upregulated miR-126 could promote the formation of contextual fear memory by modulating its target EFHD2. Finally, we demonstrated that miR-126 overexpression in dentate gyrus of hippocampus could reduce Aβ plaque area and neuroinflammation, as well as rescue the hippocampal memory deficits in APP/PS1 mice. This study adds to the growing body of evidence for the role of miRNAs in memory formation and demonstrates the implication of EFHD2 protein regulated by miR-126 in the adult brain.
Insights
MicroRNAs (miRNAs) like miR-126 are crucial for memory. This study shows miR-126 promotes fear memory consolidation by targeting EFHD2, offering potential therapeutic avenues for Alzheimer's disease (AD).
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Memory formation relies on gene expression and protein synthesis.
- MicroRNAs (miRNAs) are small noncoding RNAs regulating gene expression and are implicated in memory.
- Contextual fear memory consolidation is a key area of memory research.
Purpose of the Study:
- To investigate the role of miR-126a-3p (miR-126) in contextual fear memory consolidation.
- To identify specific Alzheimer's disease (AD)-related protein targets of miR-126.
- To explore the therapeutic potential of miR-126 in an AD mouse model.
Main Methods:
- Contextual fear conditioning (CFC) training in mice.
- Bioinformatic analysis and luciferase reporter assays to identify miRNA targets.
- Assessment of protein levels (EFHD2, BACE1) post-CFC.
- Viral vector-mediated overexpression of miR-126 in the hippocampus.
- Evaluation of Aβ plaque load, neuroinflammation, and memory function in APP/PS1 mice.
Main Results:
- miR-126 levels were elevated after CFC, correlating with memory consolidation.
- EFHD2 and BACE1 were identified as direct targets downregulated by miR-126.
- Upregulated miR-126 promoted contextual fear memory formation by modulating EFHD2.
- miR-126 overexpression in APP/PS1 mice reduced Aβ plaques, neuroinflammation, and rescued memory deficits.
Conclusions:
- miR-126 plays a significant role in the consolidation of contextual fear memory.
- The miR-126/EFHD2 pathway is a novel mechanism influencing memory in the adult brain.
- Modulating miR-126 offers a potential therapeutic strategy for AD by targeting Aβ pathology and neuroinflammation.
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