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A Reporter Assay to Analyze Intronic microRNA Maturation in Mammalian Cells
Published on: June 16, 2022
In vivo regulation of amyloid precursor protein neuronal splicing by microRNAs
Pascal Smith1, Amelle Al Hashimi, Johanne Girard
1Centre de recherche du CHUQ (CHUL), Axe Neurosciences, Québec, Canada.
Abstract:
The β-amyloid peptide that accumulate in Alzheimer's disease (AD) brain derive from proteolytic processing of the amyloid precursor protein (APP). Recent evidence suggest that microRNAs (miRNAs) participate in the post-transcriptional regulation of APP expression. Because gene dosage effects of the APP gene can cause genetic AD, dysregulation of the miRNA network could contribute significantly to disease. Here, we present evidence that, besides APP expression regulation, miRNAs are equally involved in the regulation of neuronal APP mRNA alternative splicing. Lack of miRNAs in post-mitotic neurons in vivo is associated with APP exons 7 and 8 inclusion, while ectopic expression of miR-124, an abundant neuronal-specific miRNA, reversed these effects in cultured neurons. Similar results were obtained by depletion of endogenous polypyrimidine tract binding protein 1 (PTBP1) in cells, a recognized miR-124 target gene. Furthermore, PTBP1 levels correlate with the presence of APP exons 7 and 8, while PTBP2 levels correlate with the skipping of these exons during neuronal differentiation. Finally, we show that miR-124 is down-regulated in AD brain. In sum, our results suggest that specific miRNAs are involved in the fine-tuning of APP alternative splicing in neurons. Since abnormal neuronal splicing of APP affects β-amyloid peptide production, these results could contribute to the understanding of the implication of miRNAs in brain health and disease.
Insights
MicroRNAs (miRNAs) regulate amyloid precursor protein (APP) alternative splicing in neurons, impacting beta-amyloid production. Down-regulation of miR-124 in Alzheimer
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Alzheimer's disease (AD) is characterized by beta-amyloid peptide accumulation, derived from amyloid precursor protein (APP).
- MicroRNAs (miRNAs) are implicated in post-transcriptional regulation of APP expression.
- Dysregulation of miRNA networks may contribute to AD pathogenesis, particularly given APP gene dosage effects in familial AD.
Purpose of the Study:
- To investigate the role of miRNAs in regulating neuronal APP mRNA alternative splicing.
- To explore the specific involvement of miR-124 in APP splicing.
- To examine the correlation between miRNA expression, APP splicing factors, and AD pathology.
Main Methods:
- Investigated miRNA involvement in APP mRNA alternative splicing in neurons.
- Utilized in vivo and in vitro models, including cultured neurons and post-mitotic neurons.
- Assessed the effects of miR-124 expression and PTBP1/PTBP2 depletion on APP exons 7 and 8 inclusion/skipping.
- Correlated PTBP1 and PTBP2 levels with APP splicing patterns during neuronal differentiation.
- Analyzed miR-124 levels in post-mortem AD brain tissue.
Main Results:
- miRNAs regulate neuronal APP mRNA alternative splicing, influencing the inclusion of exons 7 and 8.
- Ectopic expression of miR-124 promoted exon skipping, while its absence led to exon inclusion.
- PTBP1 depletion mimicked miR-124 effects, and PTBP1/PTBP2 levels correlated with specific splicing outcomes.
- miR-124 was found to be downregulated in the brains of Alzheimer's disease patients.
Conclusions:
- Specific miRNAs, notably miR-124, play a critical role in fine-tuning APP alternative splicing in neurons.
- Aberrant neuronal APP splicing, influenced by miRNAs, can affect beta-amyloid production.
- These findings offer insights into the contribution of miRNAs to neuronal health and Alzheimer's disease.
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