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 reactivation
of Nrf2 in AD, and support the further investigation of direct Keap1 inhibitors for
the prevention of neurodegeneration in vivo.