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.

抽象的我们提出，阿尔茨海默氏病的多因素病因学中的一个早期且可能可治疗的因素 (AD) 涉及胰淀素的稳态失调，胰淀素是一种穿过血脑屏障的胰腺激素，淀粉样蛋白生成特性与 β-淀粉样蛋白 (Aβ) 肽相似，这一假设得到了支持。我们实验室和其他实验室最近的研究表明，AD 患者的大脑中存在大量胰淀素沉积物。发现 ApoE4 携带者的脑胰岛淀粉样蛋白水平高出 4 倍以上，尤其是 2 型糖尿病患者，表明胰岛淀粉样多肽在大脑中的积累与 ApoE 和代谢危险因素之间存在联系。在胰腺中表达人胰岛淀粉样多肽并敲除胰岛淀粉样多肽后，我们发现大脑中胰岛淀粉样多肽的积累是低聚胰淀素的血液水平升高可能是通过与血浆低密度相互作用而促进的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岛淀粉样多肽并进行适当的对照（目标 1）。确定减少胰淀素诱导的大脑细胞毒性的治疗靶点。干预措施将加强机械见解，同时也提供有关潜在机制的信息人类研究将阐明脑胰岛淀粉样多肽的积累和潜在的功能影响。胰淀素-APOE 和胰淀素-Aβ 相互作用导致 AD 病理（目标 2）。与肯塔基大学 AD 中心合作，该中心拥有大量的大脑、血浆和我们还与来自临床特征良好的受试者的脑脊液标本合作。伦敦大学学院皇后广场神经疾病脑库和伦敦国王学院医学研究委员会为本项目提供了大脑标本来自早期发病的家族性 AD 患者（PSEN1 和 APP 突变携带者）的大脑标本。用于阐明脑胰岛淀粉样多肽积累与 AD 型疾病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）。相互作用，我们将表达“人类”胰淀素的大鼠与 TgF344-19 AD 大鼠模型进行杂交。该项目的成功完成提供了改进诊断和定制具体方案的潜力改变/延迟/预防衰老和代谢紊乱引起的脑损伤和认知能力下降的疗法。