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Published on: December 26, 2016
Direct Keap1-Nrf2 disruption as a potential therapeutic target for Alzheimer's disease
Fiona Kerr1, Oyinkan Sofola-Adesakin1, Dobril K Ivanov2
1Institute of Healthy Ageing, and GEE, University College London, Darwin Building, Gower Street, London, United Kingdom.
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.
Insights
Targeting Keap1 (Kelch-like ECH-associated protein 1) to activate Nrf2 (Nuclear factor erythroid 2-related factor 2) shows promise for preventing neurodegeneration in Alzheimer's disease (AD). This approach avoids side effects associated with other Nrf2 activators.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator of cellular defense mechanisms and a potential therapeutic target for neurodegenerative diseases like Alzheimer's disease (AD).
- Current strategies to activate Nrf2 may lead to toxicity and detrimental pathway over-activation.
- Understanding Nrf2 inhibition mechanisms in neurodegeneration is crucial for developing safer, targeted therapies.
Purpose of the Study:
- To investigate the potential of inhibiting Kelch-like ECH-associated protein 1 (Keap1), a negative regulator of Nrf2, as a therapeutic strategy for preventing neurotoxicity in Alzheimer's disease.
- To compare the efficacy of Keap1 inhibition with other modulators of the Nrf2 pathway, such as lithium, in preventing Aβ42-induced neurotoxicity.
- To evaluate a novel direct inhibitor of the Keap1-Nrf2 binding domain for its ability to prevent synaptotoxicity.
Main Methods:
- In vivo studies using mouse models to assess the effects of Keap1 inhibition on neuronal toxicity induced by Aβ42 peptides.
- Administration of lithium to evaluate its impact on Aβ42 toxicity and its independence from the Nrf2 pathway.
- In vitro experiments with mouse cortical neurons treated with naturally-derived Aβ oligomers and a direct Keap1-Nrf2 inhibitor.
Main Results:
- Specific inhibition of Keap1 demonstrated neuroprotective effects against Aβ42 toxicity in vivo, correlating with Nrf2 activation.
- Lithium mitigated Aβ42 toxicity through Nrf2-independent mechanisms.
- A novel direct inhibitor of the Keap1-Nrf2 binding domain successfully prevented synaptotoxicity caused by Aβ oligomers in mouse cortical neurons.
Conclusions:
- Keap1 is identified as a specific and effective target for reactivating Nrf2 in the context of Alzheimer's disease.
- Direct Keap1 inhibitors represent a promising therapeutic avenue for preventing neurodegeneration with potentially fewer side effects.
- Further in vivo investigation of direct Keap1 inhibitors is warranted for Alzheimer's disease prevention strategies.
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