IGF-1 and Alzheimer's Disease

IGF-1 和阿尔茨海默病

基本信息

批准号：
10120476
负责人：
PATRICE DELAFONTAINE
金额：
$ 38万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-12-05 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10120476
关键词：
Abeta clearance Administrative Supplement Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease related dementia Alzheimer&apos s disease risk Amyloid beta-Protein Anatomy Animal Model Animals Anti-Inflammatory Agents Antiatherogenic Antioxidants Apolipoprotein E Apoptosis Area Arterial Fatty Streak Atherosclerosis Axon Blood - brain barrier anatomy Blood Vessels Brain Brain Diseases Cardiovascular Diseases Cell Differentiation process Cells Cerebral Amyloid Angiopathy Cerebral cortex Cerebrovascular Disorders Cerebrovascular system Cognition Collagen Coronary Arteriosclerosis Dendrites Deposition Development Disease Progression Endocrine Etiology Family suidae Funding Grant Growth Growth Factor High Prevalence Hippocampus (Brain)Human Hypertension Impaired cognition Impairment Infarction Inflammation Insulin Insulin Resistance Insulin Signaling Pathway Insulin-Like Growth Factor I Insulin-Like-Growth Factor I Receptor Lead Link Long-Term Effects Metabolic Metabolism Modeling Mus Neuraxis Neurodegenerative Disorders Neurofibrillary Tangles Neurons Non-Insulin-Dependent Diabetes Mellitus Observational Study Onset of illness Overweight Oxidative Stress Pathology Patients Peripheral Physiology Play Proteomics Public Health Rattus Research Resistance Risk Risk Factors Rodent Rodent Model Role Senile Plaques Serum Signal Transduction Smoking Smooth Muscle Myocytes Testing United States United States National Institutes of Health Vascular Cognitive Impairment Vascular Dementia Vascular Diseases Vascular Smooth Muscle abeta accumulation aged autocrine brain tissue cardiovascular risk factor cerebral microvasculature cerebrovascular hypercholesterolemia improved insight interest intracranial artery metabolomics mild cognitive impairment mouse model mutant neurogenesis neurovascular novel oxidant stress paracrine pleiotropism receptor response synaptogenesis tau phosphorylation transcriptomics

项目摘要

SUMMARY Alzheimer's disease and related dementias are a major public health problem in the United States and worldwide. Although the etiology is not completely understood most patients with Alzheimer's disease have evidence of vascular pathology, thus there is increasing interest in understanding the vascular contribution to cognitive impairment and Alzheimer's disease. There is a major overlap between the risk factors for vascular disease and those for Alzheimer's, including for instance, type II diabetes and insulin resistance, hypertension, hypercholesterolemia, overweight and smoking. These risk factors are major causes of intracranial vascular disease including atherosclerosis, arteriolosclerosis and cerebral amyloid angiopathy leading to infarcts and microinfarcts. Insulin like growth factor-1 (IGF-1) is an endocrine and autocrine/paracrine growth factor that has pleiotropic effects on metabolism, growth, differentiation and survival. IGF-I and its receptor are expressed in the vasculature and we have shown that IGF-I administration to hypercholesterolemic apoe-/-mice reduced vascular and systemic inflammation, oxidative stress, smooth muscle cell apoptosis and atherosclerosis. We are now testing the anti-atherogenic effects of IGF-I in familial hypercholesterolemic Rapacz pigs, a large animal model that has major advantages over rodent models because of its anatomy and physiology being much more similar to humans. IGF-I is also produced within the central nervous system, crosses the blood brain barrier and has pleiotropic neuroprotective effects. However there is significant controversy regarding the potential role of IGF-I in Alzheimer's disease. While observational studies and some rodent studies have suggested that IGF may have beneficial effects on beta- amyloid accumulation and on the risk for Alzheimer's disease, others have shown contradictory results. Evidence suggests that reduced insulin and IGF-I signaling may play a role in the development of Alzheimer's disease. As with cardiovascular disease, small animal models do not reproduce many features of human neurodegenerative diseases. Neuroanatomical studies of the pig brain have shown a much stronger resemblance between pigs and humans than between rodents and humans. We thus have a unique opportunity to study the effect of IGF-I on intracranial vascular and brain disease including large vessel atherosclerosis, arteriolosclerosis, cerebral amyloid angiopathy, infarcts and microinfarcts in a novel swine model that develops advanced vascular disease. Correlations will be established between the degree of vascular disease and the hallmarks of Alzheimer's disease, notably, beta-amyloid deposits and neurofibrillary tangles, and exploratory transcriptomic, metabolomic and proteomic analysis of vascular and brain tissues will be performed. The study should provide key insights into the development of cerebrovascular, neurovascular and Alzheimer's disease and lay the groundwork for additional large animal studies and a potential trial of IGF-1 in humans with early-stage cognitive impairment and Alzheimer's disease.

概括阿尔茨海默氏病和相关痴呆症是美国的一个主要公共卫生问题全世界。尽管病因尚不完全清楚，但大多数阿尔茨海默病患者血管病理学的证据，因此人们越来越有兴趣了解血管的贡献认知障碍和阿尔茨海默病。风险因素之间存在重大重叠血管疾病和阿尔茨海默病，包括例如 II 型糖尿病和胰岛素抵抗，高血压、高胆固醇血症、超重和吸烟。这些风险因素是导致颅内血管疾病，包括动脉粥样硬化、小动脉硬化和脑淀粉样血管病导致梗塞和微梗塞。胰岛素样生长因子-1 (IGF-1) 是一种内分泌激素自分泌/旁分泌生长因子，对新陈代谢、生长、分化和生存。 IGF-I 及其受体在脉管系统中表达，我们已经证明 IGF-I 给药对高胆固醇血症 apoe-/-小鼠减少血管和全身炎症、氧化应激、平滑肌肌细胞凋亡和动脉粥样硬化。我们现在正在家族性中测试 IGF-I 的抗动脉粥样硬化作用高胆固醇 Rapacz 猪是一种大型动物模型，与啮齿动物模型相比具有主要优势因为它的解剖学和生理学与人类更加相似。 IGF-I 也产生于中枢神经系统，穿过血脑屏障，具有多效性神经保护作用。然而，关于 IGF-I 在阿尔茨海默病中的潜在作用存在重大争议。尽管观察性研究和一些啮齿动物研究表明 IGF 可能对 β- 关于淀粉样蛋白积累和阿尔茨海默氏病的风险，其他人得出了相互矛盾的结果。有证据表明，胰岛素和 IGF-I 信号传导减少可能在阿尔茨海默病的发展中发挥作用疾病。与心血管疾病一样，小动物模型无法再现人类的许多特征神经退行性疾病。猪脑的神经解剖学研究表明，猪脑具有更强的猪和人类之间的相似性高于啮齿动物和人类之间的相似性。因此我们拥有独特的有机会研究 IGF-I 对颅内血管和脑部疾病（包括大血管）的影响新型猪的动脉粥样硬化、小动脉硬化、脑淀粉样血管病、梗塞和微梗塞发展为晚期血管疾病的模型。将在程度之间建立相关性血管疾病和阿尔茨海默病的特征，特别是β-淀粉样蛋白沉积和神经原纤维缠结，以及血管和脑组织的探索性转录组学、代谢组学和蛋白质组学分析将被执行。这项研究应该为脑血管的发展提供重要的见解，神经血管和阿尔茨海默氏病，并为其他大型动物研究和 IGF-1 在患有早期认知障碍和阿尔茨海默病的人类中的潜在试验。