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

通过抑制Shc胰岛素增敏作为一种新的阿尔茨海默病治疗策略。 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， 病理机制是通过神经胰岛素抵抗（NIR）。我会专门研究这种病理机制 ApoE 4与胰岛素受体（IR）结合的动力学和作用，我将测试胰岛素增敏性Shc 阻断剂可以挽救胰岛素信号传导，下游线粒体代谢，神经病理学， 以及ApoE 4依赖性AD的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抑制剂是否具有作为新型AD治疗剂的潜力 战略 AD分为2类，家族性和散发性。散发性甲状腺癌的主要病理生理学假说 AD占AD病例的>95%，是淀粉样蛋白级联假说，但该假说是由 1%的家族性AD病例中存在的突变。我们调查了一个偶发性的替代假设， AD，NIR假说。这一假设假定AD主要是一种代谢功能障碍疾病， 近红外光谱的改善可以有积极的治疗效果。ApoE 4等位基因是 增加遗传散发性AD风险的最强驱动因素1-4。虽然有很多理论认为ApoE 4 影响AD病理生理学，一个具有实质性支持的假设是ApoE 4驱动NIR 5-10， 下游神经元葡萄糖代谢11 -13，以及这些胰岛素信号传导和随后的代谢 损伤驱动ApoE 4的AD病理机制6 - 10，14 -20。最近，发表的研究和我的初步数据 表明ApoE 4蛋白结合IR并损害胰岛素信号传导5，8，21。然而，我们缺乏一种机械的 了解ApoE 4如何驱动NIR。我的研究填补了这一知识空白。我的工作 一种假设是ApoE 4结合IR，驱动NIR，并引起代谢紊乱，导致AD 病理生理学 在目的1中，我研究了ApoE-IR结合动力学、位点和这种结合的功能效应，以评估其对ApoE-IR的影响。 与AD的病理生理学相关性。在目标2中，我测试是否开发了新的胰岛素增敏性Shc阻滞剂 通过Cortopassi实验室可以挽救胰岛素信号，代谢，神经病理学和记忆的参数 ApoE 4依赖性AD模型的认知功能。本研究的目的是了解 NIR、ApoE 4和AD之间的联系（目的1）以及胰岛素增敏性Shc阻滞剂是否可以挽救病理 和ApoE 4依赖性AD的临床体征（Aim 2）。这一新的治疗假设的阐述可能 开辟了一个新的战略，在AD治疗研究的基础上，而不是溶解淀粉样蛋白，而是神经， 代谢改善

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.