The Role of Apolipoprotein E4 in Neuronal Insulin Resistance and Alzheimer's Disease

抑制Shc作为一种新的阿尔茨海默病治疗策略的胰岛素敏化。 载脂蛋白E4是散发性阿尔茨海默病(AD)最强的遗传危险因素，也是一种潜在的 其发病机制是通过神经元胰岛素抵抗(NIR)实现的。我将调查这一病理机制，特别是 载脂蛋白E4与胰岛素受体(IR)结合的动力学和效应，我将测试胰岛素增敏Shc 阻滞剂可以挽救胰岛素信号、下游线粒体代谢、神经病理学、 以及ApoE4依赖的AD细胞和动物模型中的记忆和认知。这项研究将进一步 描述ApoE-IR在细胞中的结合，并确定Shc抑制剂是否有潜力作为一种新的AD治疗药物 策略。 AD分为家族性和偶发性两类。散发性疾病的主要病理生理学假说 AD，占AD病例的95%，是淀粉样级联假说，但这个假说是推导出来的 来自1%的家族性阿尔茨海默病患者的突变。我们研究了零星的另一种假说。 AD，近红外假说。这一假说认为，阿尔茨海默病主要是一种代谢紊乱的疾病，由 NIR的改善可以产生积极的治疗效果。ApoE4等位基因是 遗传性散发性AD风险增加的最大驱动力1-4。虽然有许多关于载脂蛋白E4如何 影响AD的病理生理学，一个有实质性支持的假说是ApoE4驱动NIR 5-10，损害 下游神经元葡萄糖代谢11-13，以及这些胰岛素信号和随后的代谢 损伤驱动载脂蛋白E4‘S AD病理机制6-10，14-20。最近发表的研究和我的初步数据 提示ApoE4蛋白结合IR并损害胰岛素信号通路5，8，21。然而，我们缺乏一种机械的 了解ApoE4如何推动近红外。我的研究解决了这一知识鸿沟。我的工作 假设ApoE4结合IR，驱动NIR，并引起代谢紊乱，从而导致AD 病理生理学。 在目标1中，我研究了载脂蛋白E-IR的结合动力学、结合部位和这种结合的功能效应，以评估其 阿尔茨海默病的病理生理学相关性。在目标2中，我测试了新的胰岛素增敏Shc阻滞剂是否已经开发出来 科托帕西实验室可以挽救胰岛素信号、新陈代谢、神经病理和记忆的参数 以及对载脂蛋白E4依赖AD模型的认知。这项研究的目的是了解其机制。 NIR、ApoE4和AD(Aim 1)之间的联系以及胰岛素增敏Shc阻滞剂是否可以挽救病理 和载脂蛋白E4依赖型AD的临床体征(目标2)。对这一新的治疗假说的阐述可能 开启AD治疗研究的新策略，不是基于淀粉样蛋白的溶解，而是基于神经- 改善新陈代谢。

Insulin Sensitization by Shc Inhibition as a Novel Alzheimer's Disease Therapeutic Strategy. Apolipoprotein E4 is the strongest genetic risk factor for sporadic Alzheimer’s Disease (AD) and a potential pathomechanism is via neuronal insulin resistance (NIR). I will investigate this pathomechanism, specifically the kinetics and effect of binding of ApoE4 to insulin receptor (IR), and I will test if insulin-sensitizing Shc blockers can rescue parameters of insulin signaling, downstream mitochondrial metabolism, neuropathology, and memory and cognition in cell and animal models of ApoE4-dependent AD. This research will further describe ApoE-IR binding in cells and establish if Shc inhibitors have potential as a novel AD therapeutic strategy. AD is split into 2 categories, familial and sporadic. The dominant pathophysiological hypothesis for sporadic AD, which accounts for >95% of AD cases, is the amyloid cascade hypothesis but this hypothesis is derived from mutations present in the 1% of cases of familial AD. We investigate an alternative hypothesis for sporadic AD, the NIR hypothesis. This hypothesis posits that AD is primarily a disease of metabolic dysfunction, driven by NIR, and that amelioration of NIR can have positive therapeutic outcomes. The ApoE4 allele is the strongest driver of increased genetic sporadic AD risk 1–4. While there are many theories on how ApoE4 impacts AD pathophysiology, one hypothesis with substantial support is ApoE4 drives NIR 5–10, impairs downstream neuronal glucose metabolism11–13, and these insulin signaling and consequent metabolic impairments drive ApoE4's AD pathomechanism6–10,14–20. Recently, published studies and my preliminary data suggest that ApoE4 protein binds IR and impairs insulin signaling5,8,21. However, we lack a mechanistic understanding of how ApoE4 drives NIR. My research addresses this gap in knowledge. My working hypothesis is that ApoE4 binds IR, drives NIR, and causes metabolic perturbations that contribute to AD pathophysiology. In Aim 1 I investigate ApoE-IR binding kinetics, site, and the functional effect of this binding to assess its pathophysiological relevance to AD. In Aim 2 I test whether novel insulin-sensitizing Shc blockers developed by the Cortopassi lab can rescue parameters of insulin signaling, metabolism, neuropathology, and memory and cognition in models of ApoE4-dependent AD. The goal of this research is to understand the mechanistic connection between NIR, ApoE4, and AD (Aim 1) and if insulin-sensitizing Shc blockers can rescue pathology and clinical signs of ApoE4-dependent AD (Aim 2). The elaboration of this novel therapeutic hypothesis could open a new strategy in AD therapeutic research not based on dissolution of amyloid, but rather on neuro- metabolic improvement.