Does E4orf1 prevent further deterioration in Alzheimer's disease pathology in older mice

E4orf1是否可以防止老年小鼠阿尔茨海默病病理进一步恶化

• 批准号: 10303933
• 负责人: Vijay Karkal Hegde
• 金额: $ 18.64万
• 依托单位: TEXAS TECH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10303933
• 关键词: APP-PS1; Address; Adenoviruses; Adipocytes; Adipose tissue; Age-Months; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid beta-Protein; Antidiabetic Drugs; Applications Grants; Attenuated; Basic Science; Biochemical; Brain; Brain region; Bypass; Cessation of life; Chronic; Clinical; Clinical Management; Clinical Sciences; Clinical Trials; Cognition; Data; Degenerative Disorder; Dementia; Deterioration; Development; Diabetes Mellitus; Diet; Disease; Disease Progression; Distal; Doxycycline; Drug usage; Early Diagnosis; Early treatment; Exploratory/Developmental Grant; Functional disorder; Funding; GCG gene; Glucose; Goals; Grant; Hepatocyte; Hippocampus (Brain); Human; Hyperglycemia; Hyperinsulinism; Hypothalamic structure; Impaired cognition; Impairment; Insulin; Insulin Receptor; Insulin Resistance; Intervention; Learning; Link; Longitudinal Studies; Mediating; Memory; Metabolism; Mitochondria; Modeling; Molecular; Mus; Neurobehavioral Manifestations; Neurodegenerative Disorders; Neurologic; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Pathogenicity; Pathway interactions; Peripheral; Pharmaceutical Preparations; Prevention; Preventive treatment; Process; Production; Proteins; Reducing Agents; Research; Risk Factors; Role; Skeletal Muscle; Synapses; Testing; Therapeutic; Transgenic Model; Work; adiponectin; age related; cognitive function; design; effective therapy; epidemiology study; glucose disposal; glucose metabolism; glucose output; glucose uptake; glycemic control; high risk; improved; insulin secretion; insulin signaling; mitochondrial dysfunction; mouse model; neuropathology; novel; novel therapeutics; prevent; receptor; response; success; synaptic function; tool; treatment strategy

PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD), is a neurodegenerative disease with associated cognitive decline, dementia and eventual death. There has been significant advancement in our understanding of AD neuropathology, however, there are no therapeutic strategies that consistently relieve cognitive symptoms or prevent, cure or slow its progression. Interestingly, a number of well-designed epidemiological studies have established a link between Type 2 Diabetes (T2D), a chronic, age-related degenerative disorder and AD, identifying T2D as a risk factor for developing all cause dementia and dementia attributable to AD. T2D and AD, together with other neurological conditions, share several clinical and biochemical features. Particularly important amongst these is impaired insulin signaling, suggesting overlapping pathogenic mechanisms. Hence, an effective treatment strategy in one disease could have potential value in the other. Several clinical and basic science studies have shown that anti-diabetic medications can improve cognitive function. Despite promise, none of these strategies have resulted in improving our understanding or effective treatment options. The long-term goal is to dissect shared mechanisms between T2D and AD regulating the molecular pathways in AD progression. These discoveries will facilitate discover effective treatment strategies to prevent AD or its progression. Previous treatment strategies either act in the periphery or directly in the brain, raising the question if peripheral as well as central glycemic control needs to be targeted for influencing AD. Therefore, the central hypothesis is that peripheral hyperinsulinemia contributes to brain insulin resistance and cognitive decline, and that alleviating hyperinsulinemia in both periphery and brain regions will reduce AD-related molecular deterioration. The overall objective of this exploratory grant is to harness the ability of adenoviral protein E4orf1 to reduce peripheral and central hyperinsulinemia and hyperglycemia to attenuate AD progression. The rationale is that restoring normal insulin action and prevention of further impairment in cognition decline will help identify mechanisms to offer new therapeutic opportunities. Using the endogenous insulin sparing action of adenoviral protein E4orf1, the aims will elucidate a previously unidentified therapeutic approach for the effective treatment of AD. This is a paradigm shift from previously used anti-diabetic approaches for AD treatment and will help modify currently available therapies or identify new options for prevention and better clinical management of AD.

项目总结/摘要 阿尔茨海默病（Alzheimer's disease，AD）是一种神经退行性疾病，伴有认知功能减退、痴呆 最终死亡我们对AD神经病理学的理解有了显著的进步， 然而，没有持续缓解认知症状或预防、治愈或 减缓其进程。有趣的是，一些精心设计的流行病学研究已经建立了一个联系， 2型糖尿病（T2 D）是一种慢性、年龄相关性退行性疾病， 发展为全因痴呆和归因于AD的痴呆的危险因素。T2 D和AD，以及其他 神经系统疾病，共享几个临床和生化特征。其中尤为重要的是 是胰岛素信号传导受损，提示重叠的致病机制。因此，有效的治疗 一种疾病的治疗策略可能对另一种疾病有潜在的价值。一些临床和基础科学研究已经 显示抗糖尿病药物可以改善认知功能。尽管有希望，但这些策略中没有一个 提高了我们的认识或有效的治疗方案。长期目标是解剖 T2 D和AD之间的共同机制调节AD进展中的分子途径。这些 这些发现将有助于发现预防AD或其进展的有效治疗策略。先前 治疗策略要么作用于外周，要么直接作用于大脑，这就提出了一个问题， 因为中枢血糖控制需要作为影响AD的目标。因此，中心假设是， 外周高胰岛素血症有助于脑胰岛素抵抗和认知能力下降， 外周和脑区域的高胰岛素血症将减少AD相关的分子恶化。的 这项探索性资助的总体目标是利用腺病毒蛋白E4 orf 1的能力， 外周和中枢高胰岛素血症和高血糖症以减弱AD进展。基本原理是 恢复正常的胰岛素作用和防止认知功能进一步下降将有助于识别 提供新的治疗机会。利用腺病毒的内源性胰岛素节省作用， 蛋白E4 orf 1，目的将阐明一个以前未确定的有效治疗方法 的AD。这是一个范式的转变，从以前使用的抗糖尿病方法治疗AD， 修改目前可用的治疗方法或确定新的预防和更好的临床管理方法， AD.