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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos 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

项目摘要

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.

项目概要/摘要阿尔茨海默病 (AD) 是一种神经退行性疾病，伴有认知能力下降、痴呆以及最终的死亡。我们对 AD 神经病理学的理解取得了重大进展，然而，没有治疗策略可以持续缓解认知症状或预防、治愈或减缓其进展。有趣的是，一些精心设计的流行病学研究已经建立了联系 2 型糖尿病 (T2D)（一种与年龄相关的慢性退行性疾病）与 AD 之间的研究，将 T2D 视为一种发生全因痴呆和 AD 所致痴呆的危险因素。 T2D 和 AD 以及其他神经系统疾病具有一些共同的临床和生化特征。其中尤为重要的是胰岛素信号传导受损，表明致病机制重叠。因此，有效的治疗针对一种疾病的策略可能对另一种疾病具有潜在价值。多项临床和基础科学研究研究表明，抗糖尿病药物可以改善认知功能。尽管有承诺，但这些策略都没有提高了我们的理解或有效的治疗方案。长期目标是剖析 T2D 和 AD 之间调节 AD 进展分子途径的共同机制。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。以前的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：外周是否也起作用因为需要以中央血糖控制为目标来影响 AD。因此，中心假设是外周高胰岛素血症会导致大脑胰岛素抵抗和认知能力下降，从而缓解外周和大脑区域的高胰岛素血症将减少 AD 相关的分子恶化。这这项探索性资助的总体目标是利用腺病毒蛋白 E4orf1 的能力来减少外周和中枢高胰岛素血症和高血糖，以减轻 AD 进展。理由是恢复正常的胰岛素作用并防止认知能力进一步下降将有助于识别提供新的治疗机会的机制。利用腺病毒的内源性胰岛素节约作用蛋白质 E4orf1，目的将阐明一种先前未确定的有效治疗方法公元。这是对以前用于 AD 治疗的抗糖尿病方法的范式转变，并将有助于修改当前可用的疗法或确定新的预防方案和更好的临床管理广告。