Intranasal Insulin in a Mouse Model of Alzheimer's Disease

阿尔茨海默病小鼠模型中的鼻内胰岛素

基本信息

批准号：
9050620
负责人：
WILLIAM A BANKS
金额：
$ 49.55万
依托单位：
SEATTLE INST FOR BIOMEDICAL/CLINICAL RES
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9050620
关键词：
Adverse effects Affect Aftercare Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid beta-Protein Amyloid beta-Protein Precursor Antibodies Apoptosis Blood - brain barrier anatomy Brain Brain region Bypass Cell Death Characteristics Clinical Research Cognition Cognitive Cognitive deficits Defect Dose Drug Kinetics Effectiveness Functional disorder Future Gene Expression Germany Goals Health Hippocampus (Brain)Human Impaired cognition Impairment In Vitro Insulin Insulin Receptor Insulin Resistance Intranasal Administration Kinetics Label Lead Learning Literature Measures Mediation Memory Memory impairment Metabolic Metabolism Modeling Mus Nasal cavity Oxidative Stress Patients Peptides Peripheral Phenotype Process Radioactive Radioimmunoassay Route Site Tauopathies Testing Tg2576 Therapeutic Time Tissues Vascular Diseases Work aged cholinergic cribriform plate design disease phenotype drug discovery experience feeding improved in vivo insulin sensitivity/resistance insulin sensitizing drugs mouse model neurogenesis neuroinflammation neuron loss neurotoxicity receptor receptor expression receptor function receptor sensitivity research study response rosiglitazone synaptogenesis tau Proteins uptake

项目摘要

DESCRIPTION (provided by applicant): Although several clinical studies from two different groups have shown that insulin when given by the intranasal (INL) route results in an almost immediate improvement in cognition in Alzheimer's disease (AD) patients that is sustainable to at least 4 mo, there is very little work examining how INL insulin works. Our preliminary results show that radioactive insulin (I-Ins) reaches the hippocampus after INL administration in mice through a saturable mechanism and that INL insulin improves both learning and memory in an AD mouse model (the aged SAMP8 mouse) at doses that do not affect peripheral metabolism. The cognitive effect of INL insulin is evident in the SAMP8 within 24 h, but new preliminary results submitted in this A1 show further improvement in cognition when INL insulin is repeatedly administered for 2 weeks. In this application, we will examine in the aged SAMP8 mouse three critical aspects that are important to understanding how INL acts in AD, testing the widely held hypothesis that AD is a state in which CNS insulin action is deficient. In SA1, we will determine the pharmacokinetics and brain distribution of transport of INL administered insulin in the SAMP8. In SA2, we will determine the status of hippocampal insulin receptor expression and function, determining if the aged SAMP8 has CNS insulin resistance. In SA3, we will determine the effects of INL insulin on the AD phenotype as expressed by the aged SAMP8 [increased brain amyloid beta load and vasculopathy , tauopathy, BBB dysfunctions (decreased bulk flow of CSF; P-gp and LRP-1 efflux deficits), cholinergic defect, and oxidative stress], determine the types of cognitive deficits remediable by INL insulin, and determine the effects of INL insulin on gene expression, and hippocampal cell death , synaptogenesis, and neurogenesis. We will also compare the effects of immediate (24 h after treatment) and sustained (2 weeks of treatment) INL insulin administration on key aspects of the phenotype. Overall, these studies will for the first time define how INL insulin works in an AD model.

描述（由申请人提供）：尽管来自两个不同组的几项临床研究表明，当鼻内（INL）途径给予时，胰岛素几乎可以立即改善阿尔茨海默氏病（AD）患者的认知，至少可持续至至少4个月，但很少有工作能够检查INL胰岛素的工作方式。我们的初步结果表明，放射性胰岛素（I-INS）通过可饱和机制在INL给药后到达海马，并且INL胰岛素以不影响外周代谢的剂量的AD小鼠模型（老年SAMP8小鼠）的学习和记忆改善了学习和记忆。 INL胰岛素的认知作用在24小时内很明显，但是当INL胰岛素反复施用2周时，A1中提交的新初步结果显示出认知的进一步改善。在此应用程序中，我们将在老年SAMP8小鼠中检查三个关键方面，这些方面对于了解INL在AD中的作用至关重要，并检验了广泛持有的假设，即AD是CNS胰岛素作用不足的状态。在SA1中，我们将确定SAMP8中INL胰岛素施用的药代动力学和大脑分布。在SA2中，我们将确定海马胰岛素受体表达和功能的状态，确定老年SAMP8是否具有CNS胰岛素抵抗。在SA3中，我们将确定INL胰岛素对AD表型的影响，如老年SAMP8（增加了脑淀粉样蛋白β载荷和脉管病，tauopathy，BBB功能障碍（CSF的批量流量减少； P-GP和LRP-1外排）的批量降低； P-gp和LRP-1外排），巧克力固定的定义，以及氧气的定义，以及氧气的降低，以及氧气的延迟，以及氧气的延迟[csf和LRP-1外的缺陷]，以及氧气的范围，以及氧气的固定范围，以及氧气的定义，以及氧气的辩护，以及氧气的辩护，以及氧气的辩护，以及氧气的辩护，以及氧气的辩护，以及氧气的辩护，以及氧气的辩护，以及氧气的辩护。通过INL胰岛素，并确定INL胰岛素对基因表达以及海马细胞死亡，突触发生和神经发生的影响。我们还将比较立即（治疗后24小时）和持续（治疗2周）INL胰岛素对表型的关键方面的影响。总体而言，这些研究将首次定义INL胰岛素在AD模型中的工作方式。