Inhibitor Kappa B Kinase β, Modulated by DJ-1/p-VHL, Reduces Phosphorylated Tau (p-Tau) Accumulation via Autophagy in...

It has been demonstrated Inhibitor Kappa B Kinase β (IKKβ) facilitates autophagy, which in turn mediates p-Tau protein clearance. However, the specific regulatory mechanism in Alzheimer's disease (AD) remains unclear. Firstly, AD model was generated by the intracerebroventricular (ICV) injection of the Β-amyloid 1-42 (Aβ_1-42) peptide. Subsequently, mice were injected with shRNA adenoviral transduction particles designed to target DJ-1 or Aβ_1-42 or Aβ_1-42 + shNC or Aβ_1-42 + shRNA against DJ-1. shRNA against DJ-1 were injected into hippocampus of mice (8 × 10⁴ viral particles for each mice) for seven consecutive days. Immunohistochemistry was performed to detect the accumulation of Aβ in the hippocampus of mice, and Hematoxylin-Eosin (HE) staining assay was carried to detect pathological changes in the hippocampus of mice. Further, sh-IKKβ, shDJ-1, pcDNA-IKKβ and pcDNA-DJ-1 plasmids were transfected into HT-22 cells, MTT assay, TUNEL staining and Hoechst staining were performed to detect cell viability and apoptosis, respectively. Western blotting was carried to measure the relative expression of proteins. Findings indicated that Aβ_1-42 inhibited autophagy and up-regulated p-Tau protein expression; Overexpression of IKKβ and DJ-1 all rescued the autophagy inhibited by Aβ_1-42 and down-regulated p-Tau protein expression induced by Aβ_1-42; DJ-1 up-regulated IKKβ via p-VHL, further promoted autophagy and reduced the expression of p-Tau protein; DJ-1 knockdown inhibited autophagy and up-regulated p-Tau protein expression, resulting in delayed behavior in mice. In conclusion, IKKβ, modulated by DJ-1/p-VHL, reduces p-Tau accumulation via autophagy in AD's disease model. This study may provide theoretical basis for the treatment of AD.