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

• 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
• 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' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' 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

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 使用一种新型的离体刺激方法，可以测量脑对胰岛素的反应，我们的研究 在2012年建立的小组在与痴呆症病例中非常普遍和深刻的绝对性密切相关 随着认知能力的加速下降。异常是脑胰岛素抵抗，许多人可以诱导许多 AD中的早期致病因素（包括全身性胰岛素抵抗），进而导致或加剧 其后来的许多病理特征和认知缺陷。因此，脑胰岛素抵抗似乎是淋巴结 AD的异常，其缓解可能通过对A的疗法施加疗法的影响来减缓疾病进展的异常 广泛的病理范围，从而慢慢的AD认知下降。如果是这样，可以通过 减少脑胰岛素抵抗。 可用于降低脑胰岛素耐药性的最有前途的药物中，是相对新的药物 抗糖尿病类别称为增量受体激动剂（IRA），已经知道可以降低全身性 胰岛素抵抗。 IRA激活2个主要增加受体中的一个或两个：胰高血糖素样肽-1受体 （GLP-1R）和葡萄糖依赖性胰岛素多肽受体（GIPR）。至少有3个Iras越过血液 - 脑屏障，即两种GLP-1R激动剂（Exendin-4和Liraglutide）和一个最近开发的双重GLP- 1R/GIPR激动剂（即双IRA）。然后，在中枢神经系统外管理，这些IRA可以减少两者 在后一种情况下，通过激活GLP-1R和GIPR尤其是在后一种情况下，尤其是在后一种情况下， AD病例的脆弱区域，包括新皮层和海马形成。我们的初步数据显示 IRA从轻度认知障碍（MCI）病例明显地将离体应用于海马形成 在大脑结构中降低胰岛素抵抗，并且双重IRA即使在高级AD中也具有这种影响 痴呆症（加）病例。 鉴于这些引人注目的发现，我们提出了对AD可以通过的假设进行的临床前评估 减少IRA的脑胰岛素耐药性。我们的方法在测试候选AD疗法方面具有创新性 它们对AD动物模型和实际AD（和MCI）对脑组织的身体影响 案例。我们的候选疗法（Exendin-4，Liraglutide和Dual IRA）将在3个目标大脑区域进行测试 在AD（a）野生型和 APP/PS1小鼠和（B）正常，MCI，并添加病例。 AIM 1将确定相对效率和 3种IRA候选者的药代动力学在降低大脑胰岛素抵抗和到达的能力方面 通过其正常皮下给药途径靶向大脑区域。 AIM 2将测试分子机制 这些药物通过其中降低脑胰岛素抵抗。 AIM 3将测试IRA诱导的脑胰岛素减少 抗性与广泛的AD相关病理的降低密切相关（例如，Aβ升高 磷酸化的tau增加，脑葡萄糖利用率降低）和空间记忆缺陷。