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

摘要 使用一种新的体外刺激方法来测量大脑对胰岛素的反应，我们的研究 该小组成立于2012年，与阿尔茨海默病非常常见和严重的异常病例密切相关 伴随着认知功能的加速衰退。这种异常是大脑胰岛素抵抗，它可以由许多因素引起 阿尔茨海默病的早期致病因素(包括全身性胰岛素抵抗)，进而可引起或加重 它的许多后来的病理特征和认知缺陷。因此，大脑胰岛素抵抗似乎是一个结节 阿尔茨海默病阿尔茨海默病中的一种异常现象，其缓解可通过对 广泛的病理改变，从而减缓阿尔茨海默病的认知能力下降。如果是这样的话，有可能通过以下方式治疗AD 降低大脑胰岛素抵抗。 最有希望降低大脑胰岛素抵抗的药物是一种相对较新的药物 一类抗糖尿病药物，称为胰岛素受体激动剂(IRAs)，已知可降低全身性 胰岛素抵抗。IRA激活两种主要的胰岛素受体中的一种或两种：胰升糖素样肽-1受体 (GLP-1R)和葡萄糖依赖的促胰岛素多肽受体(GIPR)。至少有3个IRA穿过血液- 脑屏障，即两种GLP-1R激动剂(埃森丁-4和利拉鲁肽)和最近开发的双重GLP-1R- 1R/GIPR激动剂(即双IRA)。然后，在中枢神经系统外使用这些IRA可以减少这两种 全身性和脑性胰岛素抵抗，后者通过激活GLP-1R和GIPR而发生，尤其是 阿尔茨海默病患者的易感区域，包括新皮质和海马结构。我们的初步数据显示 IRAS在轻度认知障碍(MCI)患者海马区的体外应用 减少大脑结构中胰岛素抵抗，即使在晚期AD患者，双重IRA也有这种效果 痴呆症(ADD)病例。 鉴于这些惊人的发现，我们建议对阿尔茨海默病可以通过以下方法治疗的假设进行临床前评估 使用IRAs降低脑内胰岛素抵抗。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)脑组织的生理影响 案子。我们的候选疗法(exendin-4、利拉鲁肽和双IRA)将在3个目标脑区进行测试。 在AD(外侧前额叶皮质、后顶叶皮质和海马结构)中，来自(A)野生型和 APP/PS1小鼠和(B)正常、MCI和ADD病例。目标1将确定相对疗效和 3种IRA候选药物降低脑胰岛素抵抗的药代动力学及其达标能力 通过正常的皮下给药途径靶向大脑区域。AIM 2将测试分子机制 通过这些药物降低大脑的胰岛素抵抗。AIM 3将测试IRA是否导致脑内胰岛素减少 耐药性与广泛的AD相关病理改变密切相关(例如，Aβ升高， 磷酸化tau增加，大脑葡萄糖利用减少)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.