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Intrahippocampal Inoculation of Aβ1-42 Peptide in Rat as a Model of Alzheimer's Disease Identified MicroRNA-146a-5p
Ruth Aquino1,2,3, Vidian de Concini4, Marc Dhenain5
1Centre de Biophysique Moléculaire, CNRS UPR 4301, Rue Charles Sadron CS 80054, CEDEX 02, 45071 Orléans, France.
Abstract:
Circulating microRNAs (miRNAs) have aroused a lot of interest as reliable blood diagnostic biomarkers of Alzheimer's disease (AD). Here, we investigated the panel of expressed blood miRNAs in response to aggregated Aβ1-42 peptides infused in the hippocampus of adult rats to mimic events of the early onset of non-familial AD disorder. Aβ1-42 peptides in the hippocampus led to cognitive impairments associated with an astrogliosis and downregulation of circulating miRNA-146a-5p, -29a-3p, -29c-3p, -125b-5p, and-191-5p. We established the kinetics of expression of selected miRNAs and found differences with those detected in the APPswe/PS1dE9 transgenic mouse model. Of note, miRNA-146a-5p was exclusively dysregulated in the Aβ-induced AD model. The treatment of primary astrocytes with Aβ1-42 peptides led to miRNA-146a-5p upregulation though the activation of the NF-κB signaling pathway, which in turn downregulated IRAK-1 but not TRAF-6 expression. As a consequence, no induction of IL-1β, IL-6, or TNF-α was detected. Astrocytes treated with a miRNA-146-5p inhibitor rescued IRAK-1 and changed TRAF-6 steady-state levels that correlated with the induction of IL-6, IL-1β, and CXCL1 production, indicating that miRNA-146a-5p operates anti-inflammatory functions through a NF-κB pathway negative feedback loop. Overall, we report a panel of circulating miRNAs that correlated with Aβ1-42 peptides' presence in the hippocampus and provide mechanistic insights into miRNA-146a-5p biological function in the development of the early stage of sporadic AD.
Insights
This study identifies circulating microRNAs (miRNAs) as potential biomarkers for early Alzheimer's disease (AD). We found specific miRNAs change in rats with amyloid-beta peptides, revealing insights into AD pathogenesis and miRNA-146a-5p's anti-inflammatory role.
Area of Science:
- Neuroscience
- Molecular Biology
- Biomarkers
Background:
- Circulating microRNAs (miRNAs) are promising blood-based biomarkers for Alzheimer's disease (AD).
- Early detection of sporadic AD is crucial for effective intervention.
- Amyloid-beta (Aβ) peptide aggregation is a key pathological feature in AD.
Purpose of the Study:
- To investigate circulating miRNA expression in response to Aβ1-42 peptide infusion in a rat model mimicking early AD.
- To explore the mechanistic role of miRNA-146a-5p in astrocyte inflammatory responses.
- To identify potential blood diagnostic biomarkers for early-stage sporadic AD.
Main Methods:
- Infusion of Aβ1-42 peptides into the rat hippocampus to induce AD-like pathology.
- Profiling of circulating miRNAs and assessment of cognitive function, astrogliosis, and inflammatory markers.
- In vitro studies using primary astrocytes treated with Aβ1-42 and miRNA inhibitors to elucidate signaling pathways (NF-κB).
Main Results:
- Aβ1-42 induced cognitive impairment, astrogliosis, and downregulation of specific circulating miRNAs (e.g., miRNA-146a-5p, -29a-3p, -29c-3p).
- miRNA-146a-5p was exclusively dysregulated in the Aβ-induced model and upregulated in astrocytes via NF-κB activation.
- miRNA-146a-5p demonstrated anti-inflammatory functions by negatively regulating the NF-κB pathway, impacting cytokine production.
Conclusions:
- A panel of circulating miRNAs, including miRNA-146a-5p, correlates with hippocampal Aβ1-42 presence in an early AD model.
- miRNA-146a-5p plays a critical anti-inflammatory role in astrocytes through a negative feedback loop in the NF-κB pathway.
- These findings highlight potential circulating miRNA biomarkers for early sporadic AD and offer mechanistic insights into disease development.
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