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Published on: March 16, 2016
MicroRNA-155-5p Targets SKP2, Activates IKKβ, Increases Aβ Aggregation, and Aggravates a Mouse Alzheimer Disease
Wei Wang1, Xun-Hu Gu1, Min Li1
1From the Department of Neurology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China.
Abstract:
The nuclear factor kappa B (NF-κB) pathway and inhibitor of NF-κB kinase β (IKKβ) are involved in Alzheimer disease (AD) pathogenesis. This study explored the mechanisms underlying IKKβ-mediated Aβ aggregation and neuron regeneration in APP.PS1 mice. Adenoviral transduction particles were injected into the hippocampal CA1 region of the mice to knock down or inhibit target genes. Morris water maze was performed to evaluate the cognitive function of the mice. Aβ deposition was determined by histological examination. sh-IKKβ plasmids and microRNA (miR)-155-5p inhibitor were transfected into Aβ1-42-induced N2a cells. The expressions of AD-related proteins were detected by Western blot. The interaction between S-phase kinase-associated protein 2 (SKP2) and IKKβ was assessed by co-immunoprecipitation. IKKβ knockdown (KD) and miR-155-5p inhibition ameliorated cognitive impairment, improved neuron regeneration, and attenuated Aβ deposition in APP/PS1 mice. SKP2 KD aggravated cognitive impairment, inhibited neuron regeneration, and promoted Aβ deposition in the mice. SKP2 regulated the stability of IKKβ protein via ubiquitination. MiR-155-5p regulates Aβ deposition and the expression of Aβ generation-related proteins in N2a cells via targeting SKP2. These results indicate that the miR-155-5p/SKP2/IKKβ axis was critical for pathogenesis in this AD model and suggest the potential of miR-155-5p as a target for AD treatment.
Insights
This study reveals that inhibiting microRNA-155-5p and S-phase kinase-associated protein 2 (SKP2) can improve cognitive function and reduce amyloid-beta (Aβ) aggregation in Alzheimer's disease (AD) models. The miR-155-5p/SKP2/IKKβ pathway is crucial for AD pathogenesis.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- The nuclear factor kappa B (NF-κB) pathway and inhibitor of NF-κB kinase β (IKKβ) are implicated in Alzheimer's disease (AD) pathogenesis.
- Understanding the molecular mechanisms driving Aβ aggregation and neurodegeneration is critical for developing effective AD therapies.
Purpose of the Study:
- To investigate the role of IKKβ in Aβ aggregation and neuron regeneration within an AD mouse model.
- To elucidate the regulatory interactions between miR-155-5p, SKP2, and IKKβ in the context of AD.
Main Methods:
- Utilized adenoviral transduction in APP.PS1 mice to manipulate gene expression in the hippocampus.
- Assessed cognitive function using the Morris water maze and quantified Aβ deposition via histological examination.
- Employed cell-based assays with N2a cells to analyze protein expression, ubiquitination, and interactions using Western blot and co-immunoprecipitation.
Main Results:
- Knockdown of IKKβ (IKKβ KD) and inhibition of miR-155-5p significantly improved cognitive function, enhanced neuron regeneration, and reduced Aβ deposition in APP/PS1 mice.
- SKP2 knockdown exacerbated cognitive deficits, impaired neurogenesis, and increased Aβ burden, indicating its critical role.
- SKP2 was found to regulate IKKβ protein stability through ubiquitination, and miR-155-5p targets SKP2 to influence Aβ-related protein expression.
Conclusions:
- The miR-155-5p/SKP2/IKKβ signaling axis is a key determinant of pathogenesis in this Alzheimer's disease model.
- Targeting miR-155-5p presents a promising therapeutic strategy for Alzheimer's disease treatment.
