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

载脂蛋白 E4 在神经元胰岛素抵抗和阿尔茨海默病中的作用

• 批准号: 10680417
• 负责人: Chase A Garcia
• 金额: $ 4.04万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10680417
• 关键词: Address; Affect; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Alzheimer' s disease therapeutic; Alzheimer' s disease therapy; American; Amyloid; Animal Model; Apolipoprotein E; Binding; Binding Proteins; Binding Sites; Biological Assay; Brain; Categories; Cause of Death; Cell model; Cells; Clinical; Cognition; Confusion; Coupled; Data; Defect; Dementia; Detection; Disease; Doctor of Philosophy; Dose; Enzyme-Linked Immunosorbent Assay; Functional disorder; Genetic; Genus Hippocampus; Glucose; Goals; Hippocampus; Histopathology; Impaired cognition; Impairment; In Vitro; Insulin; Insulin Receptor; Insulin Resistance; Interferometry; Intervention; Investigation; Kinetics; Knowledge; Laboratories; Link; Literature; Long-Term Potentiation; Measures; Mediating; Memory; Memory Loss; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolism; Mitochondria; Modeling; Mus; Mutation; Neurodegenerative Disorders; Neurologic; Neurons; Pathology; Phosphorylation; Phosphotyrosine; Physiological; Proteins; Public Health; Publishing; Receptor Activation; Receptor Signaling; Research; Resolution; Role; Senile Plaques; Signal Pathway; Signal Transduction; Site; Testing; Therapeutic; Therapeutic Research; age related; aged; aging brain; apolipoprotein E-3; apolipoprotein E-4; drug development; familial Alzheimer disease; genetic risk factor; glucose metabolism; improved; in vivo; inhibitor; insulin sensitivity; insulin sensitizing drugs; insulin signaling; mitochondrial metabolism; mouse model; neurobehavioral; neurobehavioral test; neuronal metabolism; neuropathology; novel; novel therapeutics; object recognition; oxidation; receptor binding; research and development; response; theories; therapeutic development; therapy outcome

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.

通过 Shc 抑制使胰岛素增敏作为一种新型阿尔茨海默氏病治疗策略。 载脂蛋白 E4 是散发性阿尔茨海默病 (AD) 最强的遗传风险因素，也是潜在的 病理机制是通过神经元胰岛素抵抗（NIR）。我将具体研究这种病理机制 ApoE4 与胰岛素受体 (IR) 结合的动力学和效果，我将测试 Shc 是否具有胰岛素增敏作用 阻滞剂可以挽救胰岛素信号、下游线粒体代谢、神经病理学的参数， ApoE4 依赖性 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 抑制剂是否具有作为新型 AD 治疗药物的潜力 战略。 AD分为两类：家族性和散发性。散发性的主要病理生理学假说 AD 占 AD 病例的 95% 以上，是淀粉样蛋白级联假说，但该假说源自 1% 的家族性 AD 病例中存在突变。我们研究了零星事件的替代假设 AD，近红外假说。该假说认为 AD 主要是一种代谢功能障碍疾病， 通过 NIR 进行检测，改善 NIR 可以产生积极的治疗结果。 ApoE4 等位基因是 遗传性散发性 AD 风险增加的最强驱动因素 1-4。虽然关于ApoE4如何发挥作用有很多理论 影响 AD 病理生理学，一项得到充分支持的假设是 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传导和随后的代谢 损伤驱动 ApoE4 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 ApoE4 蛋白结合 IR 并损害胰岛素信号5,8,21。然而我们缺乏一个机制 了解 ApoE4 如何驱动 NIR。我的研究解决了这一知识空白。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 ApoE-IR 结合动力学、位点以及该结合的功能效应，以评估其 与 AD 的病理生理学相关性。在目标 2 中，我测试是否开发出新型胰岛素增敏 Shc 阻滞剂 Cortopassi 实验室的研究可以挽救胰岛素信号、新陈代谢、神经病理学和记忆的参数 ApoE4 依赖性 AD 模型中的认知和认知。这项研究的目的是了解其机制 NIR、ApoE4 和 AD 之间的联系（目标 1）以及胰岛素增敏 Shc 阻滞剂是否可以挽救病理 以及 ApoE4 依赖性 AD 的临床症状（目标 2）。这种新的治疗假说的阐述可以 在 AD 治疗研究中开辟了一种新策略，不是基于淀粉样蛋白的溶解，而是基于神经元 代谢改善。