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Novel target for treating Alzheimer's Diseases: Crosstalk between the Nrf2 pathway and autophagy

Weiwei Zhang1, Cong Feng1, Hong Jiang1

  • 1Department of Health Laboratory Technology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning 110122, People's Republic of China.

Ageing Research Reviews
|November 4, 2020
PubMed

Insights

The Keap1-Nrf2-ARE pathway and autophagy, linked by p62, protect cells from oxidative damage. Maintaining this p62-Keap1-Nrf2 feedback loop may treat neurodegenerative diseases like Alzheimer's.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Neuroscience

Background:

  • The Keap1-Nrf2-ARE pathway and autophagy are critical cellular defense systems against oxidative stress and for maintaining homeostasis.
  • p62/SQSTM1 acts as a crucial link between the Nrf2 pathway and autophagy, mediating the interaction between Keap1 and Nrf2.
  • Dysregulation of this pathway is implicated in neurodegenerative diseases, including Alzheimer's disease (AD).

Purpose of the Study:

  • To elucidate the role of the p62-Keap1-Nrf2 positive feedback loop in cellular defense mechanisms.
  • To investigate the involvement of the Nrf2 pathway and autophagy in the context of neurodegenerative diseases.
  • To explore the therapeutic potential of targeting the p62-Keap1-Nrf2 pathway for AD treatment.

Main Methods:

  • Investigated the molecular interactions between p62, Keap1, and Nrf2.
  • Examined the role of p62 phosphorylation in regulating Keap1-Nrf2 binding and subsequent Nrf2 activation.
  • Studied the involvement of selective autophagy (LC3 recruitment) in Keap1 degradation.
  • Analyzed the positive feedback loop created by Nrf2-mediated upregulation of p62.
  • Correlated p62-activated Nrf2 pathway activity with markers of neurodegeneration.

Main Results:

  • Phosphorylation of p62 enhances its affinity for Keap1, leading to Nrf2 release and subsequent nuclear translocation.
  • The p62-Keap1 heterodimer recruits LC3, facilitating Keap1 degradation via selective autophagy.
  • A positive feedback loop is established where Nrf2 upregulates p62 expression, amplifying cellular protection.
  • The p62-activated Nrf2 pathway is identified as a significant marker in neurodegenerative diseases.
  • This pathway is involved in clearing reactive oxygen species (ROS) and protein aggregates in AD.

Conclusions:

  • The p62-Keap1-Nrf2 positive feedback loop is a vital bridge between the Nrf2 pathway and autophagy, crucial for cellular defense.
  • This pathway plays a significant role in mitigating oxidative damage and protein aggregation characteristic of AD.
  • Maintaining the homeostasis of the p62-Keap1-Nrf2 pathway presents a promising therapeutic target for Alzheimer's disease and other neurodegenerative conditions.
Keywords:
Alzheimer’s diseaseAutophagyNrf2 pathwayOxidative stressp62-Keap1-Nrf2 positive feedback loop

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