IGF-1 and Alzheimer's Disease

摘要 阿尔茨海默病和相关痴呆症是美国的一个主要公共卫生问题， 全世界。虽然病因还不完全清楚，但大多数阿尔茨海默病患者都有 血管病理的证据，因此人们对了解血管的作用越来越感兴趣 认知障碍和阿尔茨海默病。在以下风险因素之间有很大的重叠 血管疾病和阿尔茨海默氏症的疾病，包括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、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)是一种内分泌和 自分泌/旁分泌生长因子对新陈代谢、生长、分化和 生死存亡。IGF-I及其受体在血管系统中表达，我们已经证明IGF-I的应用 对高胆固醇血症APOE-/-小鼠降低血管和全身炎症、氧化应激、通畅 肌细胞凋亡与动脉粥样硬化。我们现在正在测试胰岛素样生长因子-I的抗动脉粥样硬化作用。 高胆固醇血症的Rapacz猪，一种比啮齿动物模型更具优势的大型动物模型 因为它的解剖学和生理学与人类非常相似。IGF-I也是在 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仍存在重大争议。而当 观察性研究和一些啮齿动物研究表明，IGF可能对β-氨基丁酸有有益的影响。 在淀粉样蛋白堆积和阿尔茨海默病风险方面，其他研究人员显示了相互矛盾的结果。 有证据表明，胰岛素和IGF-I信号的减少可能在阿尔茨海默氏症的发展中起作用 疾病。与心血管疾病一样，小动物模型不能复制人类的许多特征 神经退行性疾病。对猪脑的神经解剖学研究表明， 猪和人之间的相似性大于啮齿动物和人之间的相似性。因此，我们拥有一种独特的 研究胰岛素样生长因子-I在包括大血管在内的脑血管疾病中作用的机会 一种新型猪的动脉粥样硬化、动脉硬化、脑淀粉样血管病变、脑梗塞和微梗塞 发展为晚期血管疾病的模型。将在以下程度之间建立关联： 血管疾病和阿尔茨海默病的特征，特别是β-淀粉样沉积和神经原纤维 以及血管和脑组织的探索性转录、代谢和蛋白质组学分析 将会被执行。这项研究应该为脑血管的发展提供关键的见解， 神经血管和阿尔茨海默病，为更多的大型动物研究和 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。

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.