Modulation of TNFα as a Treatment for Alzheimer's Disease and Related Dementia

标题：调节 TNFα 作为阿尔茨海默病和相关痴呆的治疗方法 摘要 越来越多的证据表明，年龄相关的认知障碍和相关痴呆症的一个主要决定因素， 是大脑胰岛素依赖型糖尿病和血管健康。虽然阿尔茨海默病（AD）是最常见的 痴呆症的一种形式，其特征是淀粉样斑块和 TAU 病理学，针对这些的临床试验 病理学尚未成功。研究表明 AD 病例与糖尿病和脑血管疾病共存 病理学。在正常生理情况下，胰岛素通过葡萄糖转运蛋白介导葡萄糖转运至细胞内； 然而，在病理生理条件下，胰岛素受体信号变得不敏感，导致 代谢功能障碍。与这些变化共存的是脑血管病变，表现为 血流量减少、中风和微梗塞。尽管有这些观察结果，但很少有临床试验研究大脑 胰岛素依赖性代谢减退和相关的血管功能障碍。我们和其他人相信新陈代谢 血管失调可以被认为是一系列具有共同途径的痴呆症的始作俑者 的激活。通过衰老改善或保持新陈代谢和脑血管健康可能会降低风险或 预防认知障碍和痴呆。我们假设调节肿瘤坏死因子 α（TNFα）途径将保护脑代谢并维持血管和健康。肿瘤坏死因子α 通路是免疫信号传导的关键调节因子，已被证明随着年龄的增长而增强。而且，最近 研究表明，TNFα 通过 TNFα 受体（TNFR1 和 TNFR2）介导的作用与 随着年龄的增长和痴呆，观察到糖酵解和血管失调。我们实验室之前的工作有 发现携带 APOEE4/E4 的小鼠表现出灌注和葡萄糖代谢随年龄的解偶联，类似 人类患者群体中也报道了该表型。因此，这笔赠款将使用携带 APOEE4/E4，我们将通过两种不同的方法调节 TNFα 信号传导。在目标 1 中，我们将确定 APOEE3/E4 变体是否表现出与 APOEE4/E4 类似的神经血管功能障碍，因为这在 人口。如果是这样，我们将利用它来实现所有后续目标。然后我们将使用 TNFα 的定时消融 通过使用新开发的 B6.TNFαflox/flox 小鼠与他莫昔芬诱导型 cre、CAGGCre- ER（JAX 库存号#004682）确定全局基因 TNFα 消融是否会导致脑血管的保存 功能。这将使用高度转化的临床测量（例如 PET/CT）进行评估。血液和组织将 收集用于生化和分子分析。在目标 2 中，我们将采取补充干预措施 使用 R-7050 作为工具化合物来阐明 TNFR1 信号传导在代谢和血管中的作用 通过破坏 TNFR1-TRADD-RIP1 信号转导而导致功能障碍。综合这些数据将为我们奠定基础 探索 TNFα 信号在 AD 及相关代谢和血管功能障碍中的分子机制 痴呆症。

TITLE: Modulation of TNFα as a Treatment for Alzheimer’s Disease and Related Dementia ABSTRACT Growing evidence suggest a major determinant of age-related cognitive impairment, and associated dementia, is cerebral insulin dependent diabetes and vascular health. While Alzheimer’s disease (AD) is the most common form of dementia, and is characterized by amyloid plaques and TAU pathology, clinical trials targeting these pathologies have not been successful. Studies show AD cases are comorbid with diabetes and cerebrovascular pathology. Under normal physiology, insulin mediates glucose transport into the cell via the glucose transporter; however, in pathophysiological conditions, the insulin receptor signal becomes desensitized, resulting in metabolic dysfunction. Comorbid with these changes are cerebrovascular pathologies, which manifest as reduced blood flow, strokes, and micro-infarcts. Despite these observations, few clinical trials have studied brain insulin dependent hypometabolism and associated vascular dysfunction. We, and others, believe that metabolic and vascular dysregulation can be considered initiators of a spectrum of dementias that share common pathways of activation. Improving or preserving metabolism and cerebrovascular health through aging may reduce risk or prevent cognitive impairment and dementia. We hypothesize that modulating the Tumor Necrosis Factor alpha (TNFα) pathway will preserve cerebral metabolism and maintain vascular and health. The TNFα pathway is a key regulator in immune signaling, which has been shown to increase with age. Moreover, recent studies have shown that TNFα mediated action via the TNFα receptors (TNFR1 and TNFR2) is implicated in the glycolytic and vascular dysregulation observed with advancing age and dementia. Previous work in our lab has identified that mice carrying APOEE4/E4 show uncoupling of perfusion and glucose metabolism with age, similar to the phenotype also reported in the human patient population. Therefore, this grant will use mice carrying APOEE4/E4, and we will modulate TNFα signaling through two different approaches. In Aim 1, we will determine whether the APOEE3/E4 variant show similar neurovascular dysfunction as APOEE4/E4, as this is more common in the human population. If so, we will utilize this for all subsequent aims. We will then use timed ablation of TNFα through the use of a newly developed B6.TNFαflox/flox mouse paired with a tamoxifen inducible cre, CAGGCre- ER (JAX stock #004682) to determine if global genetic TNFα ablation leads to preservation of cerebrovascular function. This will be assessed using highly translational clinical measure such as PET/CT. Blood and tissue will be collected for biochemical and molecular analyses. In Aim 2, we will take a complementary interventional approach using R-7050 as a tool compound to elucidate the role of TNFR1 signaling in metabolic and vascular dysfunction by disrupting TNFR1-TRADD-RIP1 signal transduction. Combined these data will lay the groundwork for exploring the molecular mechanisms of TNFα signal in metabolic and vascular dysfunction in AD and related dementias.