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.

已经证明抑制剂κB激酶β（IKKβ）促进自噬，其继而介导p-Tau蛋白清除。但是，阿尔茨海默氏病（AD）的具体调节机制仍不清楚。首先，通过脑室内（ICV）注射β-淀粉样蛋白1-42（_Aβ1-42）肽生成AD模型。随后，给小鼠注射旨在针对DJ-1的DJ-1或_Aβ1–42或_Aβ1–42  + shNC或_Aβ1–42  + shRNA的shRNA腺病毒转导颗粒。将针对DJ-1的shRNA注入小鼠海马体中（8×10 ⁴每只小鼠的病毒颗粒）连续7天。进行免疫组织化学检测小鼠海马中Aβ的积累，并用苏木精-曙红（HE）染色法检测小鼠海马中的病理变化。此外，将sh-IKKβ，shDJ-1，pcDNA-IKKβ和pcDNA-DJ-1质粒转染到HT-22细胞中，进行MTT测定，TUNEL染色和Hoechst染色以分别检测细胞活力和凋亡。进行蛋白质印迹以测量蛋白质的相对表达。结果表明，_Aβ1–42抑制自噬并上调p-Tau蛋白表达。IKKβ和DJ-1的过度表达均可挽救_Aβ1–42抑制的自噬，并下调Aβ诱导的p-Tau蛋白表达_1–42；DJ-1通过p-VHL上调IKKβ，进一步促进自噬并降低p-Tau蛋白的表达。DJ-1组合式抑制自噬和上调p-Tau蛋白表达，从而导致小鼠行为延迟。总之，由DJ-1 / p-VHL调节的IKKβ通过自噬减少了AD疾病模型中的p-Tau积累。该研究可为AD的治疗提供理论依据。