Intranasal Insulin in a Mouse Model of Alzheimer's Disease

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，胰岛素经鼻内（INL）途径给药后，几乎立即改善阿尔茨海默病（AD）患者的认知功能，并可持续至少4个月，但很少有研究INL胰岛素如何发挥作用。我们的初步结果表明，放射性胰岛素（I-Ins）通过饱和机制到达小鼠INL给药后的海马，并且INL胰岛素在不影响外周代谢的剂量下改善AD小鼠模型（老年SAMP 8小鼠）的学习和记忆。在SAMP 8中，INL胰岛素的认知效应在24小时内是明显的，但在本A1中提交的新的初步结果显示，当INL胰岛素重复给药2周时，认知进一步改善。在本申请中，我们将在老年SAMP 8小鼠中研究三个关键方面，这对于理解INL在AD中的作用非常重要，测试了广泛持有的假设，即AD是CNS胰岛素作用不足的状态。在SA 1中，我们将 确定SAMP 8中INL给药胰岛素转运的药代动力学和脑分布。在SA 2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SAMP 8是否具有CNS胰岛素抵抗。在SA 3中，我们将确定INL胰岛素对AD表型的影响，如老年SAMP 8 [脑淀粉样蛋白β负荷增加和血管病变、tau蛋白病变、BBB功能障碍]所表达的。（CSF的整体流量减少; P-gp和LRP-1外排缺陷）、胆碱能缺陷和氧化应激]，确定INL胰岛素可治疗的认知缺陷类型，并确定INL胰岛素对基因表达的影响，以及海马细胞死亡、突触发生和神经发生。我们还将比较立即（治疗后24小时）和持续（治疗2周）INL胰岛素给药对表型关键方面的影响。总体而言，这些研究将首次定义INL胰岛素在AD模型中的作用方式。

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.