Treating Alzheimer's disease by reducing brain insulin resistance with incretin receptor agonists

通过肠促胰岛素受体激动剂降低大脑胰岛素抵抗来治疗阿尔茨海默病

基本信息

批准号：
10229324
负责人：
GREGORY M COLE
金额：
$ 19.34万
依托单位：
LOMA LINDA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-15 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10229324
关键词：
APP-PS1 Acute Affect Agonist Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease therapeutic Amyloid beta-Protein Animal Disease Models Animal Model Animals Antidiabetic Drugs Area Blood - brain barrier anatomy Blood Vessels Brain Brain Pathology Cerebrum Chronic Clinical Trials Design Cognition Cognitive deficits Data Development Diabetes Mellitus Disease Disease Progression Dose Drug Kinetics Drug resistance Endoplasmic Reticulum Evaluation GLP-I receptor Gastric Inhibitory Polypeptide Gene Expression Glucose Hippocampal Formation Hour Impaired cognition Inflammation Inflammatory Insulin Insulin Receptor Insulin Resistance Lateral Leptin Literature Measurement Mediating Memory impairment Methods Molecular Mus Neocortex Nodal Oxidative Stress Parietal Lobe Pathologic Pathology Peripheral Pharmaceutical Preparations Physiological Prefrontal Cortex Receptor Activation Research Route Structure Subcutaneous Injections Synapses Testing Therapeutic Effect Tissues Transgenic Mice Virulence Factors base brain tissue cytokine drug action drug efficacy exenatide experimental study gastric inhibitory polypeptide receptor glucagon-like peptide 1 glucose uptake innovation insulin receptor substrate 1 protein intravenous injection liraglutide mild cognitive impairment novel preclinical evaluation protein function public health relevance receptor resistance mechanism response spatial memory subcutaneous tau-1 therapeutic candidate uptake

项目摘要

Abstract Using a novel ex vivo stimulation method allowing measurement of brain responses to insulin, our research group established in 2012 a very common and profound abnormality in AD dementia cases closely associated with accelerated cognitive decline. That abnormality is brain insulin resistance, which can be induced by many early pathogenic factors in AD (including systemic insulin resistance) and can in turn cause or exacerbate many of its later pathologic features and cognitive deficits. Brain insulin resistance thus appears to be a nodal abnormality in AD, one whose alleviation may slow disease progression by exerting therapeutic effects on a broad spectrum of pathologies and thereby slow cognitive decline in AD. If so, it may be possible to treat AD by reducing brain insulin resistance. Among the most promising agents available for reducing brain insulin resistance are drugs in a relatively new class of antidiabetics known as incretin receptor agonists (IRAs), which are already known to reduce systemic insulin resistance. IRAs activate one or both of the 2 major incretin receptors: glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR). At least 3 IRAs cross the blood- brain barrier, namely two GLP-1R agonists (exendin-4 and liraglutide) and a recently developed dual GLP- 1R/GIPR agonist (i.e., a dual IRA). Administered outside the CNS, then, these IRAs could reduce both systemic and brain insulin resistance, in the latter case by activating GLP-1R and GIPR found in especially vulnerable areas of AD cases, including the neocortex and hippocampal formation. Our preliminary data show that IRAs applied ex vivo to the hippocampal formation from mild cognitive impairment (MCI) cases markedly reduce insulin resistance in that brain structure and that the dual IRA has this effect even in advanced AD dementia (ADd) cases. Given these striking findings, we propose a preclinical evaluation of the hypothesis that AD can be treated by reducing brain insulin resistance with IRAs. Our approach is innovative in testing candidate AD therapeutics for their physiological effects on brain tissue from both an animal model of AD and from actual AD (and MCI) cases. Our candidate therapeutics (exendin-4, liraglutide, and a dual IRA) will be tested on 3 target brain areas in AD (lateral prefrontal cortex, posterior parietal cortex, and hippocampal formation) from (a) wild-type and APP/PS1 mice and (b) normal, MCI, and ADd cases. Aim 1 will determine the relative efficacy and pharmacokinetics of the 3 IRA candidates in reducing brain insulin resistance and their ability to reach the target brain areas via their normal subcutaneous route of administration. Aim 2 will test molecular mechanisms by which these drugs reduce brain insulin resistance. Aim 3 will test if IRA-induced reductions in brain insulin resistance are closely associated with reductions in a wide range of AD-related pathologies (e.g., elevated Aβ, increased phosphorylated tau, decreased cerebral glucose utilization) and spatial memory deficits.

抽象的我们的研究使用一种新颖的离体刺激方法来测量大脑对胰岛素的反应小组于 2012 年建立了一种与 AD 痴呆病例密切相关的非常常见且严重的异常现象这种异常现象就是大脑胰岛素抵抗，它可以由许多因素引起。 AD 的早期致病因素（包括全身胰岛素抵抗），进而导致或恶化因此，其许多后来的病理特征和认知缺陷似乎是一个节点。 AD 异常，其缓解可通过对 AD 异常发挥治疗作用来减缓疾病进展 AD 的病理范围广泛，认知能力下降缓慢。如果是这样，那么就有可能通过这种方法来治疗 AD。降低大脑胰岛素抵抗。可用于降低脑胰岛素抵抗的最有前途的药物是相对较新的药物一类称为肠促胰岛素受体激动剂 (IRA) 的抗糖尿病药，已知可减少全身性糖尿病胰岛素抵抗会激活 2 个主要肠促胰岛素受体中的一种或两种：胰高血糖素样肽 1 受体。 (GLP-1R) 和葡萄糖依赖性促胰岛素多肽受体 (GIPR) 至少有 3 个 IRA 穿过血液。脑屏障，即两种 GLP-1R 激动剂（exendin-4 和利拉鲁肽）和最近开发的双重 GLP-1R 激动剂 1R/GIPR 激动剂（即双重 IRA）在中枢神经系统外施用，这些 IRA 可以减少两者。全身性和脑部胰岛素抵抗，在后一种情况下通过激活 GLP-1R 和 GIPR 发现，特别是我们的初步数据显示，AD 病例的脆弱区域，包括新皮质和海马结构。 IRA 离体应用于轻度认知障碍 (MCI) 病例的海马结构显着降低大脑结构中的胰岛素抵抗，即使在晚期 AD 中，双重 IRA 也具有这种效果痴呆症（ADd）病例。鉴于这些惊人的发现，我们提出了对 AD 可以通过以下方法治疗的假设进行临床前评估：我们的方法在测试 AD 候选疗法方面具有创新性。它们对 AD 动物模型和实际 AD（和 MCI）脑组织的生理影响我们的候选治疗药物（exendin-4、利拉鲁肽和双重 IRA）将在 3 个目标大脑区域进行测试。 AD（外侧前额皮质、后顶叶皮质和海马结构）来自 (a) 野生型和 APP/PS1 小鼠和 (b) 正常、MCI 和 ADd 病例将确定相对功效和效果。 3 种 IRA 候选药物在降低脑胰岛素抵抗方面的药代动力学及其达到目标的能力通过正常的皮下给药途径靶向大脑区域，目的 2 将测试分子机制。目标 3 将测试 IRA 是否会导致脑胰岛素减少。耐药性与多种 AD 相关病理的减少密切相关（例如 Aβ 升高、磷酸化 tau 蛋白增加、脑葡萄糖利用率降低）和空间记忆缺陷。