Intranasal Insulin in a Mouse Model of Alzheimer's Disease

描述(申请人提供)：尽管来自两个不同组的几项临床研究表明，当胰岛素通过鼻腔(INL)途径给药时，阿尔茨海默病(AD)患者的认知能力几乎立即得到改善，并持续至少4个月，但很少有研究INL胰岛素如何起作用的工作。我们的初步结果表明，在小鼠注射INL后，放射性胰岛素(I-INS)通过饱和机制到达海马区，并且INL胰岛素在不影响外周代谢的剂量下改善了AD小鼠模型(老年SAMP8小鼠)的学习和记忆。INL胰岛素的认知效应在24小时内在SAMP8中就很明显，但在A1中提交的新的初步结果表明，重复使用INL胰岛素2周后，认知能力进一步改善。在这项应用中，我们将在老年SAMP8小鼠中检查三个关键方面，这三个方面对于了解INL在AD中的作用非常重要，验证了广泛存在的假设，即AD是一种中枢神经系统胰岛素作用不足的状态。在SA1中，我们将 测定INL-胰岛素在SAMP8体内的药代动力学和脑分布。在SA2中，我们将检测海马胰岛素受体的表达和功能状态，确定老年SAMP8是否存在中枢胰岛素抵抗。在SA3中，我们将确定INL胰岛素对老年SAMP8表达的AD表型的影响[脑淀粉样β蛋白负荷增加和血管病变，伸缩症，血脑屏障功能障碍(脑脊液体积流量减少；P-gp和LRP-1外流缺陷)，胆碱能缺陷，以及氧化应激]，确定INL胰岛素可修复的认知障碍的类型，并确定INL胰岛素对基因表达、海马细胞死亡、突触发生和神经再生的影响。我们还将比较即刻(治疗后24小时)和持续(治疗2周)INL胰岛素注射对表型关键方面的影响。总体而言，这些研究将首次确定胰岛素在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.