Neuroprotective mechanisms of Bach1-Derepression in Alzheimer’s Disease

项目摘要 阿尔茨海默病（AD）是一种不可逆转的、进行性的神经退行性疾病，会慢慢破坏 没有已知的治愈方法。虽然AD的原因尚不清楚，但大量证据表明， 氧化应激、线粒体功能障碍、神经炎症和蛋白质病都与AD有关 发病机制核因子红细胞2相关因子2（Nrf 2）是一个关键的转录因子， 多方面的反应，以调节参与AD的多种病因学途径。表达的下降 在人类和AD动物模型中观察到Nrf 2和Nrf 2相关通路的改变。 因此，Nrf 2通路的激活代表了AD中有希望的治疗方法。 不幸的是，典型的Nrf 2激活剂是亲电的，因为它们不仅与Kelch样上的半胱氨酸反应， ECH相关蛋白1（Keap 1）激活Nrf 2，但非特异性地与多种 导致副作用的细胞蛋白质。开发有效的基于Nrf 2的治疗方法的关键障碍 AD是目前缺乏了解的机制，可以安全地激活这一途径。BTB（广义- 复合物，tramtrack和bric-a-brac）和CNC（cap 'n'collar蛋白）同源1（Bach 1）是一种转录因子 抑制Nrf 2基因的表达我们建议进行严格的评估，以验证Bach 1抑制 作为AD发病机制的新治疗策略，并确定新的干预靶点。我们的中央 一种假说认为Bach 1抑制可保护AD患者的行为和神经病理学结果， Nrf 2依赖和Nrf 2非依赖机制。使用最先进的小鼠模型和新的非- 亲电Bach 1抑制剂，我们建议a）描绘Bach 1抑制在发病中的作用， AD病理学在体内的进展，B）确定Bach 1在神经元、星形胶质细胞和 小胶质细胞调节AD的发展，c）区分Bach 1和Nrf 2依赖性途径， 神经保护和d）鉴定用于治疗干预的新靶标。拟议的研究是基于 一个强有力的前提，并将提供一个严格的测试假设使用创新的药理学和遗传学 干预措施。这些结果将为Bach 1抑制剂作为一种新的治疗方法提供关键证据 靶向并验证新型非亲电子Bach 1抑制剂作为AD潜在治疗剂。

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.