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：
10491189
负责人：
Vijay Karkal Hegde
金额：
$ 22.44万
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 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10491189
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.

项目摘要/摘要阿尔茨海默氏病（AD）是一种神经退行性疾病，相关认知能力下降，痴呆症最终死亡。我们对AD神经病理学的理解取得了重大进步，但是，没有持续缓解认知症状或预防，治愈或减慢其进展。有趣的是，许多精心设计的流行病学研究已经建立了联系在2型糖尿病（T2D）之间，一种慢性，年龄相关的退行性障碍和AD，将T2D识别为发展所有原因痴呆症和痴呆症的风险因素。 T2D和AD，以及其他神经条件，具有几种临床和生化特征。在这些中尤其重要胰岛素信号受损，表明致病机制重叠。因此，有效的治疗方法一种疾病中的策略在另一种疾病中可能具有潜在的价值。一些临床和基础科学研究有表明抗糖尿病药物可以改善认知功能。尽管有希望，但这些策略都没有导致改善我们的理解或有效的治疗选择。长期目标是剖析 T2D和AD之间的共享机制调节AD进展中的分子途径。这些发现将促进发现有效的治疗策略，以防止AD或其进展。以前的治疗策略要么在周围或直接在大脑中起作用，因此提出了一个问题由于中央血糖控制需要用于影响AD的目标。因此，中心假设是外周高胰岛素血症有助于大脑胰岛素抵抗和认知能力下降，并减轻外围和大脑区域的高胰岛素血症将减少与广告相关的分子恶化。这这种探索性赠款的总体目标是利用腺病毒蛋白E4ORF1减少的能力外周和中央高胰岛素血症和高血糖减弱AD进展。理由是恢复正常的胰岛素作用并预防认知下降的进一步损害将有助于确定提供新的治疗机会的机制。使用腺病毒的内源性胰岛素保留作用蛋白质E4ORF1，目的将阐明一种先前未识别的治疗方法广告。这是从先前使用的抗糖尿病方法进行AD治疗的范式转变，将有助于修改当前可用的疗法或确定预防的新选择，并更好地临床管理广告。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

E4orf1 improves adipose tissue-specific metabolic risk factors and indicators of cognition function in a mouse model of Alzheimer's disease.

DOI：
10.1038/s41387-023-00242-6
发表时间：
2023-08-12
期刊：
NUTRITION & DIABETES
影响因子：
6.1
作者：
Khan, Md Shahjalal Hossain;Hefner, Marleigh;Reddy, Arubala;Dhurandhar, Nikhil V. V.;Hegde, Vijay
通讯作者：
Hegde, Vijay

Peripheral Mitochondrial Dysfunction: A Potential Contributor to the Development of Metabolic Disorders and Alzheimer's Disease.