SQSTM1/ p62 oligomerization contributes to Aβ-induced inhibition of Nrf2 signaling

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.