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

摘要 使用一种新的离体刺激方法，可以测量大脑对胰岛素的反应，我们的研究 2012年，一个研究小组在AD痴呆病例中建立了一个非常常见和深刻的异常， 认知能力加速下降这种异常就是脑胰岛素抵抗，它可以由许多 AD的早期致病因素（包括全身性胰岛素抵抗），并可反过来导致或加剧 许多后期病理特征和认知缺陷。因此，脑胰岛素抵抗似乎是一个节点， AD中的异常，其缓解可以通过对AD患者的神经系统施加治疗作用来减缓疾病进展。 广泛的病理，从而减缓AD的认知下降。如果是这样的话，有可能通过以下方法治疗AD： 降低大脑胰岛素抵抗。 其中最有前途的药物可用于减少脑胰岛素抵抗是药物在一个相对较新的 一类抗糖尿病药物，称为肠促胰岛素受体激动剂（IRA），已知其可降低全身性 胰岛素抵抗IRA激活2种主要肠促胰岛素受体之一或两者：胰高血糖素样肽-1受体 （GLP-1 R）和葡萄糖依赖性促胰岛素多肽受体（GIPR）。至少有三个IRA穿过血液 脑屏障，即两种GLP-1 R激动剂（exendin-4和利拉鲁肽）和最近开发的双重GLP-1 R激动剂， 1 R/GIPR激动剂（即，双重伊拉）。在CNS外给药，那么，这些IRA可以减少 全身和脑胰岛素抵抗，在后一种情况下，通过激活GLP-1 R和GIPR，特别是在 AD病例的脆弱区域，包括新皮层和海马结构。我们的初步数据显示 IRAs应用于轻度认知障碍（MCI）病例的海马结构， 降低脑结构中胰岛素抵抗，且双伊拉即使在晚期AD中也具有这种效果 痴呆（ADd）病例。 鉴于这些惊人的发现，我们提出了一个临床前评估的假设，即AD可以治疗， 用胰岛素抵抗抑制剂降低脑胰岛素抵抗。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）脑组织的生理作用 例我们的候选疗法（exendin-4、利拉鲁肽和双重伊拉）将在3个靶向脑区进行测试 在AD（外侧前额叶皮质、后顶叶皮质和海马结构）中， APP/PS1小鼠和（B）正常、MCI和ADd病例。目标1将确定相对功效， 3种伊拉候选物在降低脑胰岛素抵抗方面的药代动力学以及它们达到胰岛素抵抗的能力。 通过其正常皮下给药途径靶向脑区域。目标2将测试分子机制 通过这些药物降低大脑胰岛素抵抗。目标3将测试IRA是否诱导脑胰岛素减少 耐药性与广泛的AD相关病理的减少密切相关（例如，Aβ升高， 增加的磷酸化tau、降低的脑葡萄糖利用）和空间记忆缺陷。

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.