Nrf2/Bach1 signaling axis: A promising multifaceted therapeutic strategy for Alzheimer's disease
Priyanka Soni, Sudarshana M. Sharma, Andrew A. Pieper, Bindu D. Paul, Bobby Thomas
Abstract
Alzheimer's disease (AD) is the most prevalent form of dementia, which continues to elude effective treatment despite decades of research and numerous clinical trials. While existing therapeutic strategies have primarily targeted neuropathological hallmarks such as amyloid plaques and tau tangles, they have failed to halt disease progression, leaving patients with limited options. This persistent failure reveals a critical gap in our understanding of AD and calls for a fresh perspective - one that goes beyond the traditional targets and dives deeper into the fundamental cellular processes that drive neurodegeneration. Recent advances in molecular biology underscore the significance of nuclear factor E2-related factor 2 (Nrf2), often termed the "guardian of redox homeostasis," in the pathophysiology of AD. Nrf2 orchestrates cellular responses to oxidative stress and neuroinflammation - two interlinked pathological features of AD. In the brains of AD patients, Nrf2 activity is diminished, weakening the brain's ability to counteract oxidative damage. Additionally, the BTB and CNC homology 1 (Bach1) protein, a transcriptional repressor of Nrf2, has emerged as a potential therapeutic target. Here, we review the current landscape of clinical trials in AD and identify the limitations of the conventional approaches. We then explore the prospects of a novel approach that combines Nrf2 activation with Bach1 inhibition to achieve a multipronged defense against oxidative stress, neuroinflammation, and other molecular culprits driving AD. This innovative strategy holds promise for synergistically modulating multiple neuroprotective pathways to advance AD treatment.