SQSTM1/p62, also known as sequestosome 1 (SQSTM1) or p62, is an intracellular protein induced by stress and functions as an adaptor molecule in diverse cellular processes. Oxidative damage induced by overproduction of amyloid-β (Aβ) and the impairment of endogenous antioxidant Nrf2 signaling have been documented in the brains of Alzheimer's disease (AD) patients. The causes of the inactivation of Nrf2 signaling under Aβ-induced oxidative stress are unclear, and p62 might be involved in this process. In this study, APP/PS1 transgenic mice, Aβ intrahippocampal injection rat model, and SH-SY5Y cells were used to reveal that the alterations in the oligomeric state of p62 participated in the regulation of Nrf2 signaling under Aβ insult. The present in vivo and in vitro studies revealed that short-term treatment of Aβ activated Nrf2 signaling, while long-term Aβ treatment inhibited it through either canonical or noncanonical Nrf2 activation pathway. p62 oligomerization was largely attenuated under long-term Aβ treatment. The reduction of p62 oligomerization weakened p62 sequestration to Keap1, leading to Nrf2 signaling inhibition. Our findings provide a better understanding of p62-mediated modulation on Nrf2 activity and highlight a potential therapeutic target of p62 in AD.

中文翻译：

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SQSTM1/p62 寡聚化有助于 Aβ 诱导的 Nrf2 信号抑制

SQSTM1/p62，也称为 sequestosome 1 (SQSTM1) 或 p62，是一种由应激诱导的细胞内蛋白质，在不同的细胞过程中作为衔接分子发挥作用。已经在阿尔茨海默病 (AD) 患者的大脑中记录了由淀粉样蛋白 β (Aβ) 的过度产生和内源性抗氧化剂 Nrf2 信号传导受损引起的氧化损伤。在 Aβ 诱导的氧化应激下 Nrf2 信号失活的原因尚不清楚，p62 可能参与了这一过程。本研究利用APP/PS1转基因小鼠、Aβ海马内注射大鼠模型和SH-SY5Y细胞揭示p62寡聚态的改变参与了Aβ损伤下Nrf2信号传导的调控。目前的体内外研究表明，短期治疗 Aβ 激活了 Nrf2 信号，而长期 Aβ 治疗通过经典或非经典 Nrf2 激活途径抑制它。p62 寡聚化在长期 Aβ 治疗下大大减弱。p62 寡聚化的减少减弱了 p62 对 Keap1 的螯合，导致 Nrf2 信号传导抑制。我们的研究结果提供了对 p62 介导的 Nrf2 活性调节的更好理解，并突出了 p62 在 AD 中的潜在治疗靶点。