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miR-146a aggravates cognitive impairment and Alzheimer disease-like pathology by triggering oxidative stress through
H Zhan-Qiang1, Q Hai-Hua2, Z Chi3
1Department of General medicine, Affiliated Hospital of Chengde Medical College, Chengde 067000, China.
Introduction:
Mir-146a-5p has been widely recognized as a critical regulatory element in the immune response. However, recent studies have shown that miR-146a-5p may also be involved in the development of Alzheimer disease (AD). Regrettably, the related mechanisms are poorly understood. Here, we investigated the effects of miR-146a in mice models and SH-SY5Y cells treated with amyloid β (Aβ)1-42.
Methods:
To create a model of AD, SH-SY5Y cells were treated with Aβ1-42 and mice received intracerebroventricular injections of Aβ1-42. Then, the transcriptional levels of miR-146a were estimated by real-time PCR. We transiently transfected the miR-146a-5p mimic/inhibitor into cells and mice to study the role of miR-146a. The role of signaling pathways including p38 and reactive oxygen species (ROS) was studied by using specific inhibitors. Aβ and amyloid-beta precursor protein (APP)levels were measured by immunoblotting. Furthermore, Aβ expression was analyzed by immunofluorescence and histochemical examinations.
Results:
Aβ1-42-stimulated SH-SY5Y cells displayed increased transcriptional levels of miR-146a and APP. Moreover, the p38 MAPK signaling pathway and ROS production were activated upon stimulation with a miR-146a-5p mimic. However, treatment with a miR-146a-5p inhibitor decreased the levels of APP, ROS, and p-p38 MAPK. A similar phenomenon was also observed in the animals treated with Aβ1-42, in which miR-146a upregulation increased the expression of Aβ, p-p38, and ROS, while the inhibition of miR-146a had the opposite effect. This suggests that miR-146a increases Aβ deposition and ROS accumulation via the p-p38 signaling pathway.
Conclusions:
Our research demonstrates that miR-146a-5pa increases Aβ deposition by triggering oxidative stress through activation of MAPK signaling.
Insights
MicroRNA-146a-5p (miR-146a-5p) exacerbates Alzheimer disease by increasing amyloid-beta deposition and oxidative stress via the p38 MAPK pathway. Inhibiting miR-146a-5p offers a potential therapeutic strategy for Alzheimer disease.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- MicroRNA-146a-5p (miR-146a-5p) is a key regulator of immune responses.
- Emerging evidence suggests miR-146a-5p involvement in Alzheimer disease (AD) pathogenesis.
- The precise mechanisms linking miR-146a-5p to AD remain largely unelucidated.
Purpose of the Study:
- To investigate the role and underlying mechanisms of miR-146a in Alzheimer disease models.
- To explore the impact of miR-146a on amyloid-beta (Aβ) deposition and oxidative stress.
- To examine the involvement of the p38 MAPK signaling pathway in miR-146a-mediated AD progression.
Main Methods:
- Alzheimer disease models were established using Aβ1-42-treated SH-SY5Y cells and mice.
- miR-146a-5p levels were quantified using real-time PCR.
- miR-146a-5p mimic and inhibitor transfections were performed to modulate its activity.
- Specific inhibitors were used to assess the roles of p38 MAPK and reactive oxygen species (ROS).
- Aβ and amyloid-beta precursor protein (APP) levels were measured by immunoblotting and immunofluorescence.
Main Results:
- Aβ1-42 stimulation upregulated miR-146a and APP levels in SH-SY5Y cells.
- Overexpression of miR-146a-5p activated the p38 MAPK pathway and increased ROS production.
- Inhibition of miR-146a-5p reduced APP, ROS, and p-p38 MAPK levels.
- In vivo studies mirrored these findings, with miR-146a upregulation enhancing Aβ, p-p38, and ROS, while inhibition reversed these effects.
Conclusions:
- miR-146a-5p significantly contributes to Alzheimer disease pathology.
- miR-146a-5p promotes Aβ deposition and oxidative stress by activating the p38 MAPK signaling pathway.
- Targeting miR-146a-5p may represent a novel therapeutic approach for Alzheimer disease.
