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

Area of Science:

• Neuroscience
• Cellular Biology
• Molecular Biology

Background:

• Alzheimer's disease (AD) brains exhibit oxidative damage from amyloid-beta (Aβ) and impaired Nrf2 antioxidant signaling.
• The precise mechanisms linking Aβ-induced oxidative stress to Nrf2 inactivation remain unclear.
• Sequestosome 1 (SQSTM1), also known as p62, is an adaptor protein involved in cellular stress responses.

Purpose of the Study:

• To investigate the role of p62 alterations in regulating Nrf2 signaling under Aβ insult in Alzheimer's disease.
• To elucidate the impact of p62 oligomeric state changes on Nrf2 pathway activity.
• To identify p62 as a potential therapeutic target for AD.

Main Methods:

• Utilized APP/PS1 transgenic mice, an Aβ intrahippocampal injection rat model, and SH-SY5Y cells for in vivo and in vitro studies.
• Examined the effects of short-term and long-term amyloid-beta (Aβ) treatment on Nrf2 signaling and p62 oligomerization.
• Assessed the interaction between p62 oligomerization and Keap1 in modulating Nrf2 activity.

Main Results:

• Short-term Aβ treatment activated Nrf2 signaling, whereas long-term Aβ treatment inhibited it via canonical and noncanonical pathways.
• p62 oligomerization was significantly reduced under long-term Aβ exposure.
• Decreased p62 oligomerization weakened its sequestration to Keap1, resulting in Nrf2 signaling inhibition.

Conclusions:

• Alterations in p62 oligomeric state are critical in modulating Nrf2 signaling under Aβ-induced oxidative stress in Alzheimer's disease.
• Reduced p62 oligomerization disrupts the Nrf2 antioxidant defense mechanism in chronic Aβ exposure.
• Targeting p62 represents a promising therapeutic strategy for Alzheimer's disease treatment.