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

基本信息

批准号：
10538163
负责人：
Chase A Garcia
金额：
$ 3.92万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
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/10538163
关键词：
Address Affect Alleles Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease related dementia Alzheimer&apos s disease risk Alzheimer&apos s disease therapeutic Alzheimer&apos 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 (Brain)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 Human Experimentation 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

项目摘要

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.

SHC抑制作用作为一种新的阿尔茨海默氏病治疗策略。载脂蛋白E4是零星阿尔茨海默氏病（AD）的强大遗传危险因素和潜力病理机制是通过神经元胰岛素抵抗（NIR）。我将研究这种病理学，特别是 APOE4与胰岛素受体（IR）结合的动力学和作用，我将测试胰岛素敏感的SHC是否阻滞剂可以挽救胰岛素信号传导，下游线粒体代谢，神经病理学的参数，以及依赖APOE4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细胞中的ApoE-IR结合，并确定SHC抑制剂是否具有潜力作为新型AD疗法战略。 AD分为两类，家族性和零星。零星的主要病理生理假设 AD占AD案例> 95％的AD是淀粉样蛋白级联假设，但该假设得出从1％的家庭AD病例中存在的突变。我们研究了零星的替代假设 AD，NIR假设。该假设构成的AD是代谢功能障碍的主要疾病，驱动 NIR和NIR的改善可以具有阳性的治疗结果。 ApoE4等位基因是遗传零星AD风险增加的最强驱动力1-4。虽然有很多关于如何apoe4的理论影响AD病理生理学，一个具有大量支持的假设是APOE4驱动NIR 5-10，会损害下游神经元葡萄糖代谢11-13，这些胰岛素信号和随之而来的代谢障碍驱动APOE4的AD病毒力学6–10,14–20。最近，已发表的研究和我的初步数据建议APOE4蛋白结合IR并损害胰岛素信号5,8,21。但是，我们缺乏机械了解APOE4如何驱动NIR。我的研究解决了知识的差距。我的工作假设是APOE4结合IR，驱动NIR并引起代谢扰动，导致AD 病理生理学。在AIM 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的病理生理相关性。在AIM 2中，我测试了新型胰岛素敏感的SHC阻滞剂是否发展由Cortopassi实验室可以挽救胰岛素信号传导，代谢，神经病理学和记忆的参数和依赖APOE4依赖性AD模型的认知。这项研究的目的是了解机械 NIR，APOE4和AD之间的连接（AIM 1）以及胰岛素敏感的SHC阻滞剂是否可以营救病理和依赖于APOE4的临床体征（AIM 2）。这种新型热假设的阐述可以在AD疗法研究中开设新的策略不是基于淀粉样蛋白的溶解，而是基于神经 - 代谢改进。