MicroRNA-155-5p Targets SKP2, Activates IKKβ, Increases Aβ Aggregation, and Aggravates a Mouse Alzheimer Disease Model

Abstract

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.