# Neuroprotective mechanisms of Bach1-Derepression in Alzheimer’s Disease

> **NIH NIH RF1** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2022 · $2,253,614

## Abstract

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.

## Key facts

- **NIH application ID:** 10434394
- **Project number:** 1RF1AG077396-01
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** MICHAEL K LEE
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,253,614
- **Award type:** 1
- **Project period:** 2022-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10434394

## Citation

> US National Institutes of Health, RePORTER application 10434394, Neuroprotective mechanisms of Bach1-Derepression in Alzheimer’s Disease (1RF1AG077396-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10434394. Licensed CC0.

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