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 阿尔茨海默病 (AD) 的复杂性和多因素性质给机械治疗带来了独特的挑战 针对 AD 相关途径的研究和开发疗法，主要集中在抗体的产生或 清除，在人体试验中基本上失败了，迫切需要确定新的机制和方法。 载脂蛋白 (apo) E4（AD 的主要遗传风险因素）可降低 AD 的治疗靶点。 值得注意的是，85 岁时患 AD 的风险约为 70%。 拥有两个 apoE4 等位基因拷贝（约占人口的 2-3%），但拥有两个拷贝的人中只有约 10% 然而，约 25% 的 apoE4 纯合子在 85 岁以上仍然无症状。 控制对 apoE4 应激效应的敏感性或抵抗力的机制将有助于破译其 AD 发病机制中的作用，并可能导致治疗或预防 AD 的新疗法——该项目的重点。 该提议建立在我们实验室的四项新发现的基础上：(1) 老年雌性 apoE4 基因敲入小鼠（简称 apoE4）。 小鼠）的海马尖波波纹（SWR）事件较少，这对于记忆重放和记忆至关重要。 巩固——比apoE3敲入小鼠（称为apoE3小鼠）和更少的SWR相关的慢伽玛 (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 小鼠中相关的 CA3 SG 活性早在 5-6 个月大时就开始并预测认知缺陷 (4) 使用低水平的 SWR 相关 CA3 SG 活性作为功能生物标志物，我们得到了 正在建立两种新的 apoE4 小鼠品系——一种具有低 SWR 相关性，另一种具有高 SWR 相关性 CA3 SG 活性，分别称为 apoE4 敏感 (apoE4-S) 和 apoE4 抗性 (apoE4-R) 系，用于研究 阿尔茨海默病中对 apoE4 的痛苦作用的易感性和抵抗力的机制。 在目标 1 中，我们将在神经生理学、 在目标 2 中，我们将使用这两条线来探索行为和神经病理学水平。 确定控制 apoE4 对基因组不健康影响的易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。 从这些研究中获得的知识将有助于阐明 apoE4 在 AD 发病机制中的作用机制 并确定治疗或预防与 apoE4 相关的 AD 的潜在疗法靶点。