Soni Priyanka, Sharma Sudarshana M, Pieper Andrew A, Paul Bindu D, Thomas Bobby
Darby Children's Research Institute, Medical University of South Carolina, Charleston, SC, USA; Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA.
Department of Biochemistry and Molecular Biology and Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA.
Neurotherapeutics. 2025 Apr;22(3):e00586. doi: 10.1016/j.neurot.2025.e00586. Epub 2025 Apr 7.
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.
阿尔茨海默病（AD）是最常见的痴呆形式，尽管经过数十年的研究和众多临床试验，仍未找到有效的治疗方法。虽然现有的治疗策略主要针对淀粉样斑块和tau缠结等神经病理学特征，但它们未能阻止疾病进展，留给患者的选择有限。这种持续的失败揭示了我们对AD理解的关键差距，需要一个新的视角——一个超越传统靶点，更深入探究驱动神经退行性变的基本细胞过程的视角。分子生物学的最新进展强调了核因子E2相关因子2（Nrf2），常被称为“氧化还原稳态守护者”，在AD病理生理学中的重要性。Nrf2协调细胞对氧化应激和神经炎症——AD的两个相互关联的病理特征——的反应。在AD患者的大脑中，Nrf2活性降低，削弱了大脑对抗氧化损伤的能力。此外，BTB和CNC同源蛋白1（Bach1），一种Nrf2的转录抑制因子，已成为一个潜在的治疗靶点。在这里，我们回顾了AD临床试验的现状，并确定了传统方法的局限性。然后，我们探索了一种将Nrf2激活与Bach1抑制相结合的新方法的前景，以实现对氧化应激、神经炎症和其他导致AD的分子因素的多管齐下的防御。这种创新策略有望协同调节多种神经保护途径，推动AD治疗的进展。
