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

• 批准号: 9514755
• 负责人: WILLIAM A BANKS
• 金额: $ 42.63万
• 依托单位: SEATTLE INST FOR BIOMEDICAL/CLINICAL RES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9514755
• 关键词: Adverse effects; Aftercare; Aging; Alzheimer' s Disease; Alzheimer' 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; 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; Resistance development; Route; Site; Tauopathies; Testing; Tg2576; Therapeutic; Time; Tissues; Vascular Diseases; Work; aged; cholinergic; cribriform plate; design; disease phenotype; drug discovery; experience; experimental study; feeding; improved; in vivo; insulin sensitivity/resistance; insulin sensitizing drugs; mouse model; neurogenesis; neuroinflammation; neuron loss; neurotoxicity; public health relevance; receptor; receptor expression; receptor function; receptor sensitivity; response; rosiglitazone; synaptogenesis; tau Proteins; uptake

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，通过鼻内（INL）途径给予胰岛素几乎可以立即改善阿尔茨海默病（AD）患者的认知，并持续至少4个月，但关于INL胰岛素如何起作用的研究很少。我们的初步结果表明，放射性胰岛素（I-Ins）在给药后通过饱和机制到达小鼠海马，并且在不影响外周代谢的剂量下，INL胰岛素可以改善AD小鼠模型（老年SAMP8小鼠）的学习和记忆。INL胰岛素对SAMP8的认知作用在24小时内是明显的，但在本A1中提交的新的初步结果显示，重复使用INL胰岛素2周后，认知能力进一步改善。在本应用中，我们将在老年SAMP8小鼠中检查三个关键方面，这对于理解INL如何在AD中起作用很重要，并测试广泛持有的假设，即AD是一种中枢神经系统胰岛素作用不足的状态。在SA1中，我们将这样做

项目成果

Corrigendum to "Brain uptake pharmacokinetics of incretin receptor agonists showing promise as Alzheimer's and Parkinson's disease therapeutics" [Biochem. Pharmacol. 180 (2020) 114187].

“肠促胰素受体激动剂的脑摄取药代动力学显示出作为阿尔茨海默病和帕金森病治疗药物的前景”的勘误 [Biochem.

• DOI: 10.1016/j.bcp.2023.115474
• 发表时间: 2023
• 期刊: Biochemical pharmacology
• 影响因子: 5.8
• 作者: Salameh,ThereseS;Rhea,ElizabethM;Talbot,Konrad;Banks,WilliamA
• 通讯作者: Banks,WilliamA

Peptides and the blood-brain barrier.

• DOI: 10.1016/j.peptides.2015.03.010
• 发表时间: 2015-10
• 期刊: Peptides
• 影响因子: 3
• 作者: Banks WA

A Vagina Monologue: Mom's Stress, Bugs, and Baby's Brain.

阴道独白：妈妈的压力、虫子和宝宝的大脑。

• DOI: 10.1210/en.2015-1590
• 发表时间: 2015
• 期刊: Endocrinology
• 影响因子: 4.8
• 作者: Banks,WilliamA

Molecular Mechanisms of Intranasal Insulin in SAMP8 Mice.

• DOI: 10.3233/jad-190707
• 发表时间: 2019
• 期刊: Journal of Alzheimer's disease : JAD
• 作者: Rhea EM;Nirkhe S;Nguyen S;Pemberton S;Bammler TK;Beyer R;Niehoff ML;Morley JE;Farr SA;Banks WA
• 通讯作者: Banks WA

The Effects of Normal Aging on Regional Accumulation of Hyaluronan and Chondroitin Sulfate Proteoglycans in the Mouse Brain.

正常衰老对小鼠大脑中透明质酸和硫酸软骨素蛋白聚糖区域积累的影响。

• DOI: 10.1369/0022155418774779
• 发表时间: 2018
• 期刊: The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society
• 作者: Reed,MayJ;Damodarasamy,Mamatha;Pathan,JasmineL;Erickson,MichelleA;Banks,WilliamA;Vernon,RobertB
• 通讯作者: Vernon,RobertB