Role of Systemic Amylin Dyshomeostasis in Alzheimer's Disease

全身胰淀素稳态失调在阿尔茨海默病中的作用

• 批准号: 9346008
• 负责人: Florin Despa
• 金额: $ 37.48万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9346008
• 关键词: 4 hydroxynonenal; Abeta clearance; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloid beta-Protein; Animal Model; Apolipoprotein E; Biological Markers; Blood; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Diseases; Brain Injuries; CREB1 gene; Carnosine; Cell Culture Techniques; Cell model; Cerebrospinal Fluid; Cerebrovascular Circulation; Clinical; Clinical Data; Cognitive; Data; Dementia; Deposition; Diagnosis; Disease Progression; Early Onset Familial Alzheimer' s Disease; Eicosanoids; Etiology; Genotype; Goals; Hormones; Human; Hypertrophy; Impaired cognition; Impairment; Injectable; Injection of therapeutic agent; Injury; Interleukin-1 beta; Intervention; Kentucky; Knock-out; Knowledge; Late Onset Alzheimer Disease; Lead; Link; Lipid Peroxidation; Lipid Peroxides; London; Low-Density Lipoproteins; Malondialdehyde; Measures; Mediating; Medical Research; Membrane; Metabolic; Metabolic Diseases; Modeling; Neurologic Deficit; Non-Insulin-Dependent Diabetes Mellitus; Pancreas; Pancreatic Hormones; Pathologic; Pathology; Pathway interactions; Patients; Peptides; Peroxides; Pharmacologic Substance; Physiological; Plasma; Prevention strategy; Property; Protein Isoforms; Rattus; Research Project Grants; Rest; Risk Factors; Role; Signal Transduction; Smooth Muscle Myocytes; Specimen; Testing; Toxic effect; Transgenic Animals; Universities; Vascular Diseases; Work; apolipoprotein E-4; brain tissue; cerebrovascular; clinically relevant; college; cytotoxicity; data modeling; diabetic; diabetic rat; experimental study; human data; human disease; human tissue; inflammatory milieu; inhibitor/antagonist; insight; islet amyloid polypeptide; lipid peroxidation inhibitor; mutation carrier; nervous system disorder; neuroinflammation; neurotoxicity; neurovascular unit; novel; presenilin-1; prevent; repository; therapeutic evaluation; therapeutic target

Abstract We propose that an early and possibly treatable contributor to the multifactorial etiology of Alzheimer's disease (AD) involves dyshomeostasis of amylin, a pancreatic hormone that crosses the blood brain barrier and has amyloidogenic properties similar to those of the β-amyloid (Aβ) peptide. This hypothesis is supported by recent work from our lab and others showing large amylin deposits in brains of AD patients. Moreover, we found >4-fold higher brain amylin level in ApoE4 carriers, particularly in patients with type-2 diabetes, suggesting a link of the accumulation of amylin in the brain with ApoE and metabolic risk factors. Using rats expressing human amylin in the pancreas and amylin knockout, we found that the brain amylin accumulation is likely promoted by elevated blood levels of oligomerized amylin via the interaction with plasma low density lipoproteins and causes neuroinflammation and neurologic deficits. Here, we propose to test these ideas. Planned studies will determine physiological and functional changes in the brain using a rat model expressing human amylin in the pancreas and appropriate controls (Aim 1). We will specifically identify therapeutic targets to reduce amylin-induced cytotoxicity in the brain. Pharmaceutical interventions will reinforce mechanistic insights while also informing on mechanisms that underlie the brain amylin accumulation and potential functional effects in humans. Human studies will elucidate amylin-APOE and amylin-Aβ interactions contributing to AD pathology (Aim 2). Here, we collaborate with the University of Kentucky AD Center, which has a large repository of brain, plasma and cerebrospinal fluid specimens from clinically well-characterized subjects. We also collaborate with the Queen Square Brain Bank for Neurological Disorders of the University College of London and Medical Research Council of King's College London which provided for this project brain specimens from early onset familial AD patients (PSEN1 and APP mutation carriers). These brain specimens will be used to elucidate a potential relationship between the brain amylin accumulation and AD-type of plaque, i.e., early onset familial AD (associated with increased Aβ oligomerization) vs. late onset AD (attributed to the impaired Aβ clearance). To further elucidate the pathobiology of amylin-Aβ interaction, we crossed the “human” amylin expressing rat with the TgF344-19 rat model of AD. The successful completion of this project offers the potential to refining diagnosis and tailoring specific therapies to modify/ delay/ prevent brain injury and cognitive decline in aging and metabolic disorders.

摘要 我们认为，早期和可能可治疗的贡献者的多因素病因阿尔茨海默病， (AD)胰淀素是一种胰腺激素，能穿过血脑屏障， 与β-淀粉样蛋白（Aβ）肽类似的淀粉样蛋白生成特性。这一假设得到了 我们实验室和其他实验室最近的工作显示AD患者的大脑中存在大量胰淀素沉积。而且我们 发现ApoE 4携带者的脑胰淀素水平高出>4倍，特别是在2型糖尿病患者中， 提示胰淀素在脑中的积累与ApoE和代谢危险因素有关。使用大鼠 在胰腺中表达人胰淀素和胰淀素敲除后，我们发现脑胰淀素积累是 可能通过与血浆低密度脂蛋白相互作用，由血液中低聚胰淀素水平升高促进 脂蛋白并导致神经炎症和神经缺陷。在这里，我们建议测试这些想法。 计划中的研究将使用大鼠模型确定大脑的生理和功能变化 在胰腺中表达人胰淀素和适当的对照（目的1）。我们将特别 确定治疗靶点，以减少大脑中淀粉样蛋白诱导的细胞毒性。药物 干预措施将加强机械的见解，同时也告知机制， 脑胰淀素积累和人类潜在的功能影响。人类研究将阐明 淀粉样蛋白-APOE和淀粉样蛋白-A β相互作用促进AD病理学（目的2）。在这里，我们合作 与肯塔基州大学AD中心合作，该中心拥有大量的大脑、血浆和 来自临床特征良好的受试者的脑脊液标本。我们还与 伦敦大学学院皇后广场神经疾病脑库， 伦敦国王学院医学研究理事会为该项目提供了大脑标本 来自早发性家族性AD患者（PSEN 1和APP突变携带者）。这些大脑样本 用于阐明脑胰淀素积累和AD型之间的潜在关系， 斑块，即，早发性家族性AD（与Aβ寡聚化增加相关）与晚发性AD （归因于Aβ清除受损）。进一步阐明淀粉样蛋白-A β的病理生物学 为了验证这种相互作用，我们将表达“人”胰淀素的大鼠与AD的TgF 344 -19大鼠模型杂交。的 该项目的成功完成提供了改进诊断和定制特定 治疗以改变/延迟/预防脑损伤和老化和代谢紊乱中的认知下降。