Chu Ching-Tung, Uruno Akira, Katsuoka Fumiki, Yamamoto Masayuki
Department of Biochemistry and Molecular Biology, Tohoku Medical Megabank Organization, Tohoku University, Sendai 980-8573, Japan.
Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai 980-8573, Japan.
Antioxidants (Basel). 2024 Dec 13;13(12):1529. doi: 10.3390/antiox13121529.
Alzheimer's disease (AD) is a polygenic, multifactorial neurodegenerative disorder and remains the most prevalent form of dementia, globally. Despite decades of research efforts, there is still no effective cure for this debilitating condition. AD research has increasingly focused on transcription factor NRF2 (nuclear factor erythroid 2-related factor 2) as a potential therapeutic target. NRF2 plays a crucial role in protecting cells and tissues from environmental stressors, such as electrophiles and reactive oxygen species. Recently, an increasing number of studies have demonstrated that NRF2 is a key regulator in AD pathology. NRF2 is highly expressed in microglia, resident macrophages in the central nervous system, and contributes to neuroinflammation, phagocytosis and neurodegeneration in AD. NRF2 has been reported to modulate microglia-induced inflammation and facilitate the transition from homeostatic microglia to a disease-associated microglia subset. Genetic and pharmacological activation of NRF2 has been demonstrated to improve cognitive function. Here, we review the current understanding of the involvement of NRF2 in AD and the critical role that NRF2 plays in microglia in the context of AD. Our aim is to highlight the potential of targeting NRF2 in the microglia as a promising therapeutic strategy for mitigating the progression of AD.
阿尔茨海默病（AD）是一种多基因、多因素的神经退行性疾病，在全球范围内仍是最常见的痴呆形式。尽管经过数十年的研究努力，但对于这种使人衰弱的疾病仍没有有效的治愈方法。AD研究越来越多地将转录因子NRF2（核因子红细胞2相关因子2）作为一种潜在的治疗靶点。NRF2在保护细胞和组织免受环境应激源（如亲电试剂和活性氧）的影响方面起着关键作用。最近，越来越多的研究表明NRF2是AD病理过程中的关键调节因子。NRF2在小胶质细胞（中枢神经系统中的常驻巨噬细胞）中高度表达，并在AD的神经炎症、吞噬作用和神经退行性变中起作用。据报道，NRF2可调节小胶质细胞诱导的炎症，并促进从稳态小胶质细胞向疾病相关小胶质细胞亚群的转变。已证明NRF2的基因和药理学激活可改善认知功能。在此，我们综述了目前对NRF2在AD中的作用以及NRF2在AD背景下在小胶质细胞中所起关键作用的理解。我们的目的是强调以小胶质细胞中的NRF2为靶点作为减轻AD进展的一种有前景的治疗策略的潜力。
