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 摘要 越来越多的证据表明，与年龄相关的认知障碍和相关的痴呆症的一个主要决定因素， 是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 痴呆的一种形式，其特征在于淀粉样蛋白斑块和TAU病理，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病 病理在正常生理条件下，胰岛素通过葡萄糖转运蛋白介导葡萄糖转运进入细胞; 然而，在病理生理条件下，胰岛素受体信号变得脱敏，导致 代谢功能障碍与这些变化并存的是脑血管病变，其表现为 血流量减少中风和微梗塞尽管有这些观察结果，很少有临床试验研究大脑 胰岛素依赖性低代谢和相关的血管功能障碍。我们和其他人认为， 和血管失调可以被认为是一系列痴呆症的始作俑者， 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， 预防认知障碍和痴呆症。我们假设调节肿瘤坏死因子 肿瘤坏死因子α（TNFα）通路的作用是维持脑代谢和维持血管健康。TNFα 信号通路是免疫信号传导的关键调节因子，已显示其随年龄增加。此外，最近 研究表明，TNFα通过TNFα受体（TNFR 1和TNFR 2）介导的作用与 糖酵解和血管失调与年龄增长和痴呆症。我们实验室以前的工作 发现携带APOEE 4/E4的小鼠显示灌注和葡萄糖代谢随着年龄的增长而解偶联，类似于 与人类患者群体中也报告的表型相关。因此，这项资助将使用携带 APOEE 4/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 APOEE 3/E4变体是否显示与APOEE 4/E4相似的神经血管功能障碍，因为这在 人类人口。如果是这样，我们将把它用于所有后续目标。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的cre配对，CAGGCre- ER（JAX库存编号004682），以确定整体遗传性TNFα消融是否可保留脑血管 功能这将使用高度转化的临床指标（如PET/CT）进行评估。血液和组织 收集用于生物化学和分子分析。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TNFR 1信号传导在代谢和血管中的作用的方法 通过破坏TNFR 1-TRADD-RIP 1信号转导而导致功能障碍。结合这些数据将奠定基础 探讨TNFα信号在AD及相关疾病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.