Direct Keap1-Nrf2 disruption as a potential therapeutic target for Alzheimer’s disease

Abstract

Nrf2, a transcriptional activator of cell protection genes, is an attractive therapeutic target for the prevention of neurodegenerative diseases, including Alzheimer’s disease (AD). Current Nrf2 activators, however, may exert toxicity and pathway over-activation can induce detrimental effects. An understanding of the mechanisms mediating Nrf2 inhibition in neurodegenerative conditions may therefore direct the design of drugs targeted for the prevention of these diseases with minimal side-effects. Our study provides the first in vivo evidence that specific inhibition of Keap1, a negative regulator of Nrf2, can prevent neuronal toxicity in response to the AD-initiating Aβ42 peptide, in correlation with Nrf2 activation. Comparatively, lithium, an inhibitor of the Nrf2 suppressor GSK-3, prevented Aβ42 toxicity by mechanisms independent of Nrf2. A new direct inhibitor of the Keap1-Nrf2 binding domain also prevented synaptotoxicity mediated by naturally-derived Aβ oligomers in mouse cortical neurons. Overall, our findings highlight Keap1 specifically as an efficient target for the re-activation of Nrf2 in AD, and support the further investigation of direct Keap1 inhibitors for the prevention of neurodegeneration in vivo.

p62 promotes proliferation, apoptosis‑resistance and invasion of prostate cancer cells through the Keap1/Nrf2/ARE axis

“…It has been reported that overexpressed Keap1 is degraded through autophagy (35) and the degradation of Keap1 depends on a direct physical interaction between Keap1 and p62 (13). In addition, it has been reported that Nrf2 is degraded through the proteasomal system (35,36). The present study confirmed that the degradation of Nrf2 protein is always through the proteasomal system.…”

Nitric Oxide Engages an Anti-inflammatory Feedback Loop Mediated by Peroxiredoxin 5 in Phagocytes

“…Thus, the antioxidant response induced by RNIs plays an important protective role against chronic inflammation. The Keap1/Nrf2 axis also controls cellular adaptation to oxidative stress in cancer, neurodegenerative diseases, and liver disease (Chen et al, 2017; Eriksson et al, 2015; Kerr et al, 2017; Prigge et al, 2017; Romero et al, 2017). …”

Rosuvastatin alleviates high-salt and cholesterol diet-induced cognitive impairment in rats via Nrf2–ARE pathway

“…Moreover, increase in expression of Nrf2 has shown to protect against the progression of diseases in murine models of the aforementioned disorders. Nrf2 has also shown protective action in mammalian cells against toxicity induced my amyloid-β-42 (Aβ42) peptide [55]. Therefore, Nrf2 serves as a potential target for the treatment of neurodegenerative diseases.…”