Neuroprotective mechanisms of Bach1-Derepression in Alzheimer’s Disease - Project Summary Alzheimer’s disease (AD) is an irreversible and progressive neurodegenerative disorder that slowly destroys memory with no known cure. While the cause of AD is unknown, a large body of evidence suggests that oxidative stress, mitochondrial dysfunction, neuroinflammation, and proteinopathy are all implicated in AD pathogenesis. Nuclear-factor-erythroid 2-related factor 2 (Nrf2) is a key transcription factor that orchestrates a multifaceted response to modulate multiple etiological pathways involved in AD. A decline in the expression of Nrf2 and alteration of the Nrf2-related pathways are observed in humans and animal models of AD. Consequently, activation of the Nrf2 pathway represents a promising therapeutic approach in AD. Unfortunately, canonical Nrf2 activators are electrophiles as they not only react with cysteines on Kelch-like- ECH-associated protein 1 (Keap1) to activate Nrf2 but non-specifically react with thiol groups on a variety of cellular proteins resulting in side effects. A critical barrier to developing effective Nrf2-based therapeutics for AD is the current lack of understanding of mechanisms that can safely activate this pathway. BTB (broad- complex, tramtrack and bric-a-brac) and CNC (cap’n’collar protein) homology 1 (Bach1) is a transcription factor that represses Nrf2 gene expression. We propose to conduct a rigorous evaluation to validate Bach1 inhibition as a novel therapeutic strategy for AD pathogenesis and to identify new target(s) for intervention. Our central hypothesis is that Bach1 inhibition protects against behavioral and neuropathological outcomes in AD due to Nrf2-dependent and Nrf2-independent mechanisms. Using state of the art mouse models and novel non- electrophilic Bach1 inhibitors, we propose to a) delineate the role of Bach1 inhibition in the onset and progression of AD pathology in vivo, b) establish to what extent loss of Bach1 in neurons, astrocytes, and microglia modulate AD development, c) differentiate between Bach1- and Nrf2-dependent pathways in neuroprotection and d) identity novel targets for therapeutic interventions. The proposed studies are based on a strong premise and will provide a rigorous test of the hypothesis using innovative pharmacologic and genetic interventions. The outcomes will provide the critical evidence to justify Bach1 inhibition as a novel therapeutic target and validate novel non-electrophilic Bach1 inhibitors as potential therapeutic agents for AD.
