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

TNFα 的调节作为阿尔茨海默病和相关痴呆的治疗方法

• 批准号: 10511026
• 负责人: Gareth R Howell
• 金额: $ 46.93万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-20 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10511026
• 关键词: Ablation; Adult; Affect; Age; Age-associated memory impairment; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amyloid beta-Protein; Animal Model; Apolipoprotein E; Apoptotic; Area; Binding; Biochemical; Blood; Blood Circulation; Blood Vessels; Blood flow; Body Composition; Brain; Cause of Death; Cells; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrovascular system; Cerebrum; Clinical; Clinical Trials; Data; Death Domain; Dementia; Development; Diabetes Mellitus; Dose; Down-Regulation; Elderly; Environmental Risk Factor; Evaluation; Fostering; Functional disorder; Funding; Future; Genetic; Genotype; Glucose Transporter; Grant; Health; Human; IRS1 gene; Immune signaling; Impaired cognition; Impairment; Individual; Inflammatory; Insulin; Insulin Receptor; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Intervention; Late Onset Alzheimer Disease; Link; Measures; Mediating; Membrane; Metabolic; Metabolic dysfunction; Metabolism; Methodology; Modeling; Molecular; Molecular Analysis; Mouse Strains; Mus; NOS3 gene; Neurodegenerative Disorders; Non-Insulin-Dependent Diabetes Mellitus; PET/CT scan; Pathology; Pathway interactions; Perfusion; Persons; Pharmacologic Substance; Pharmacology; Phenotype; Physiology; Population; Prevention; Production; Protein Binding Domain; Protein-Serine-Threonine Kinases; Receptor Signaling; Regulation; Reporting; Research; Risk; Role; Senile Plaques; Signal Pathway; Signal Transduction; Signaling Molecule; Stroke; Subgroup; Superoxides; TNF gene; TNFRSF1A gene; TNFRSF1B gene; TRADD gene; Tamoxifen; Testing; Tissues; United States National Institutes of Health; Variant; Vascular Dementia; Vascular Diseases; Work; X-Ray Computed Tomography; advanced dementia; age related; aged; aging population; base; cerebrovascular; cerebrovascular health; cerebrovascular pathology; cohort; comorbidity; cytokine; desensitization; endophenotype; genetic risk factor; glucose metabolism; glucose transport; hypoperfusion; improved; inhibitor; mouse model; neuroprotection; neurovascular; novel; patient population; pharmacokinetics and pharmacodynamics; preservation; prevent; receptor; recruit; restoration; tissue regeneration; tool; tumor ablation

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.

标题：调节肿瘤坏死因子α治疗阿尔茨海默病和相关痴呆 摘要 越来越多的证据表明，年龄相关的认知障碍和相关的痴呆症是一个主要决定因素。 是大脑胰岛素依赖型糖尿病和血管健康。而阿尔茨海默病(AD)是最常见的 痴呆的形式，以淀粉样斑块和TAU病理为特征，针对这些的临床试验 病理学治疗并不成功。研究表明阿尔茨海默病患者合并糖尿病和脑血管疾病 病理学。在正常生理条件下，胰岛素通过葡萄糖转运体介导葡萄糖向细胞内的转运； 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。与这些变化并存的是脑血管病理，表现为 血流量减少，中风和微小梗塞。尽管有这些观察，但很少有临床试验研究大脑 胰岛素依赖型低代谢及相关的血管功能障碍。我们和其他人都认为新陈代谢 血管调节失调可以被认为是共同途径的痴呆症的始作俑者 激活的结果。通过衰老改善或保持新陈代谢和脑血管健康可能会降低 预防认知障碍和痴呆症。我们假设调节肿瘤坏死因子 α(肿瘤坏死因子α)途径具有维持脑代谢、维持血管和健康的作用。肿瘤坏死因子α 通路是免疫信号的关键调节因子，已被证明随着年龄的增长而增加。此外，最近 研究表明，肿瘤坏死因子α通过肿瘤坏死因子α受体(肿瘤坏死因子受体1和肿瘤坏死因子受体2)介导的作用参与了肿瘤坏死因子受体的作用。 随着年龄的增长和痴呆的增加，糖酵解和血管调节失调。我们实验室以前的工作是 发现携带APOEE4/E4的小鼠随着年龄的增长表现出血流和葡萄糖代谢的解偶联，类似的 这种表型在人类患者群体中也有报道。因此，这笔赠款将使用老鼠携带 我们将通过两种不同的途径来调节肿瘤坏死因子α信号。在目标1中，我们将确定 APOEE3/E4变异是否表现出与APOEE4/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，我们将利用这一点来实现所有后续目标。然后我们将对肿瘤坏死因子α进行定时消融。 通过使用新开发的B6肿瘤坏死因子αFLOX/FLOX小鼠与他莫昔芬可诱导的Cre配对，CAGGCre- ER(JAX STOCK#004682)，以确定全球遗传肿瘤坏死因子α消融是否导致脑血管保存 功能。这将使用高度平移的临床测量方法进行评估，例如PET/CT。血液和组织会 收集起来进行生化和分子分析。在目标2中，我们将采取补充性干预措施 以R-7050为工具化合物阐明TNFR1信号在代谢和血管中的作用 通过干扰TNFR1-Tradd-RIP1信号转导而导致功能障碍。将这些数据结合在一起将为 探讨肿瘤坏死因子α信号在阿尔茨海默病及其相关代谢和血管功能障碍中的分子机制 痴呆症。