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

基本信息

批准号：
9919474
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
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-15 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9919474
关键词：
4 hydroxynonenal Abeta clearance Aging Alleles Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer’s disease biomarker Amyloid Amyloid beta-Protein Animal Model Apolipoprotein E 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&apos s Disease Eicosanoids Etiology Genotype Goals Hormones Human Hypertrophy Impaired cognition Impairment Injections Injury Interleukin-1 beta Intervention Kentucky Knock-out Knowledge Late Onset Alzheimer Disease Lead Link Lipid Peroxidation 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

项目摘要

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.

抽象的我们建议早期的治疗促成阿尔茨海默氏病多因素病因（AD）涉及氨基链淀粉的Dyshomeostasis，这是一种穿越血脑屏障并具有的胰腺瘤淀粉样蛋白生成特性与β-淀粉样蛋白（Aβ）肽的淀粉样特性相似。该假设得到我们实验室的最新工作以及其他显示AD患者大脑中的大淀粉蛋白沉积物。而且，我们发现APOE4载体中的脑淀粉蛋白水平高4倍，尤其是在2型糖尿病患者中提示与APOE和代谢危险因素在大脑中积累的链接联系。使用老鼠在胰腺和淀粉蛋白敲除中表达人淀粉蛋白可能通过与血浆低密度的相互作用相互作用来促进血液水平升高脂蛋白并引起神经炎症和神经系统缺陷。在这里，我们建议测试这些想法。计划的研究将使用大鼠模型确定大脑的身体和功能变化在胰腺和适当的控制中表达人淀粉蛋白（AIM 1）。我们将具体确定治疗靶标，以降低淀粉蛋白诱导的大脑细胞毒性。药物干预措施将加强机械见解，同时也告知了基于的机制脑淀粉蛋白的积累和人类的潜在功能作用。人类研究将阐明氨基蛋白-APOE和淀粉蛋白-Aβ相互作用有助于AD病理学（AIM 2）。在这里，我们合作与肯塔基大学广告中心一起，该中心的大脑，等离子体和来自临床表征良好的受试者的脑脊液标本。我们还与伦敦大学学院神经疾病的女王广场脑库和伦敦国王学院的医学研究委员会，为该项目提供了大脑标本从早期发作家族性AD患者（PSEN1和APP突变载体）。这些大脑标本将用于阐明脑淀粉蛋白积累与AD型之间的潜在关系牙菌斑，即早期发作家族性AD（与Aβ低聚相关）与晚期AD （归因于Aβ清除率受损）。进一步阐明淀粉蛋白Aβ的病理生物学相互作用，我们与AD的TGF344-19大鼠模型越过了“人”淀粉蛋白的大鼠。这该项目的成功完成为精炼诊断和裁缝提供了潜力修改/延迟/预防脑损伤和代谢疾病的认知下降的疗法。