Study Susceptibility and Resistance to ApoE4 in Alzheimer's Disease

研究阿尔茨海默病中 ApoE4 的易感性和耐药性

• 批准号: 10418144
• 负责人: YADONG HUANG
• 金额: $ 263.7万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10418144
• 关键词: Abeta clearance; Abeta synthesis; Age; Age of Onset; Age-Months; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Animal Model; Behavioral; Biological Markers; Cell Nucleus; Clinical Research; Cognitive deficits; Disease; Dose; Event; Female; Genes; Genomics; Goals; Hippocampus (Brain); Homozygote; Human; Knock-in Mouse; Knowledge; Lead; Learning; Memory; Memory impairment; Modification; Mus; Nature; Pathogenesis; Pathway interactions; Persons; Population; Predisposition; Production; Resistance; Risk; Role; System; Therapeutic Intervention; aged; apolipoprotein E-3; apolipoprotein E-4; genetic risk factor; insight; neurophysiology; novel; novel therapeutics; prevent; research and development; sex; single cell technology; targeted treatment; therapeutic development; therapeutic target; therapy development; transcriptomics

SUMMARY The complexity and multifactorial nature of Alzheimer’s disease (AD) pose unique challenges for mechanistic studies and developing therapies. Efforts to target AD-related pathways, mostly focusing on Ab production or clearance, have largely failed in human trials. There is a pressing need to identify novel mechanisms and therapeutic targets for AD. Apolipoprotein (apo) E4—the major genetic risk factor for AD—lowers the age of onset in a gene dose–dependent manner. Remarkably, the risk of developing AD by age 85 is ~70% in people with two copies of the apoE4 allele (~2–3% of the population) but only ~10% in those with two copies of the apoE3 allele. However, ~25% of apoE4 homozygotes remain asymptomatic over age 85. Understanding the mechanisms that govern susceptibility or resistance to the detrimental effects of apoE4 would help decipher its roles in AD pathogenesis and could lead to new therapies to treat or prevent AD—the focus of this project. This proposal builds on four novel findings in our lab. (1) Aged female apoE4 knock-in mice (referred to apoE4 mice) have fewer hippocampal sharp wave ripple (SWR) events—which are critical for memory replay and consolidation—than apoE3 knock-in mice (referred to apoE3 mice) and less of the SWR-associated slow gamma (SG) activity that helps coordinate SWRs. (2) Reductions in SWR activity and in associated CA3 SG power predict spatial learning and memory impairments, respectively, in aged apoE4 mice. (3) Reduction of SWR- associated CA3 SG activity in apoE4 mice starts as early as 5–6 months of age and predicts cognitive deficits at 16 months of age. (4) Using low levels of SWR-associated CA3 SG activity as a functional biomarker, we have been establishing two new apoE4 mouse lines—one with low and one with high SWR-associated CA3 SG activity, referred to apoE4-susceptible (apoE4-S) and apoE4-resistant (apoE4-R) line, respectively—for studying the mechanisms underlying susceptibility and resistance to apoE4’s detrimental effects in Alzheimer’s disease. In Aim 1, we will fully characterize the apoE4-susceptible and apoE4-resistant lines at the neurophysiological, behavioral, and neuropathological levels and explore sex-dependent effects. In Aim 2, using both lines, we will determine the mechanisms that govern susceptibility or resistance to apoE4’s detrimental effects at the genomic and single-nucleus transcriptomic levels and explore sex-dependent modifications of the mechanisms. The knowledge gained from these studies will help elucidate the mechanisms of apoE4’s roles in AD pathogenesis and identify potential targets for therapies to treat or prevent AD related to apoE4.

概括 阿尔茨海默氏病（AD）的复杂性和多因素性质为机械带来了独特的挑战 研究和发展疗法。针对广告相关途径的努力，主要集中于AB生产或 清除，在人类试验中大为失败。迫切需要识别新型机制和 AD的治疗靶标。载脂蛋白（APO）E4（AD的主要遗传危险因素）降低了年龄 以基因剂量依赖性方式发作。值得注意的是，人口85岁的广告的风险在人中约为70％ 具有两个APOE4等位基因的副本（约占人口的约2–3％），但有两个副本的副本约为10％ APOE3等位基因。但是，约25％的APOE4纯合子在85岁以上仍然不对称。了解 控制APOE4有害影响的敏感性或抵抗力的机制将有助于破译其 在AD发病机理中的作用，可能导致新的治疗或预防AD的疗法 - 该项目的重点。 该提议建立在我们实验室中的四个新颖发现的基础上。 （1）老年雌性APOE4敲入小鼠（称为APOE4 小鼠的海马锋利波浪波纹（SWR）事件的较少，这对于记忆重播至关重要 合并 - 比APOE3敲入小鼠（称为APOE3小鼠），与SWR相关的慢速伽马较少 （SG）有助于协调SWR的活动。 （2）SWR活动和相关CA3 SG功率的减少 分别预测老年APOE4小鼠的空间学习和记忆障碍。 （3）SWR的减少 APOE4小鼠的相关CA3 SG活性早在5-6个月大时就开始了，并预测了认知缺陷 在16个月大。 （4）使用低水平的SWR相关CA3 SG活性作为功能生物标志物，我们有 我们正在建立两条新的APOE4小鼠线 - 一条具有低和高SWR相关的CA3 SG 分别提到APOE4-启示（APOE4-S）和APOE4抗性（APOE4-R）线的活动 - 用于研究 易感性和对APOE4对阿尔茨海默氏病的有害影响的抗性的机制。 在AIM 1中，我们将充分表征APOE4-启发性和抗ApoE4在神经生理学上， 行为和神经病理学水平并探索性依赖性作用。在AIM 2中，使用两行，我们将 确定控制基因组对APOE4有害影响的敏感性或抵抗力的机制 和单核转录组水平，并探索机制的性别依赖性修饰。这 从这些研究中获得的知识将有助于阐明APOE4在AD发病机理中的作用机制 并确定治疗或预防与APOE4相关的AD的疗法的潜在靶标。