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.

摘要 阿尔茨海默病(AD)的复杂性和多因素特性对机械学提出了独特的挑战 研究和开发治疗方法。针对AD相关途径的努力，主要集中在抗体的产生或 在人体试验中基本上都失败了。迫切需要确定新的机制和 AD的治疗靶点。载脂蛋白(Apo)E4是AD的主要遗传风险因素，它降低了AD的年龄 以基因剂量依赖的方式发病。值得注意的是，人们在85岁之前患上阿尔茨海默病的风险约为70% 有两个apoE4等位基因拷贝的人(~2-3%的人群)，但在那些拥有两个拷贝的apoE4等位基因的人中只有~10% 载脂蛋白3等位基因。然而，大约25%的apoE4纯合子在85岁以上仍然没有症状。了解 控制对apoE4有害影响的易感性或抵抗力的机制将有助于破译其 在AD发病机制中的作用，并可能导致治疗或预防AD的新疗法--这是该项目的重点。 这项建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基因敲除小鼠(简称apoE4 小鼠)有较少的海马区尖锐波纹(SWR)事件-这对记忆重放和 巩固-比apoE3敲入小鼠(指apoE3小鼠)和较少的SWR相关的慢伽马 (SG)帮助协调SWR的活动。(2)SWR活动和相关CA3 SG功率减少 分别预测老年apoE4小鼠的空间学习和记忆障碍。(3)降低驻波比- ApoE4小鼠相关的CA3SG活动早在5-6个月大时就开始了，并预示着认知障碍 在16个月大的时候。(4)使用低水平的SWR相关的CA3SG活性作为功能生物标记物，我们有 我建立了两个新的apoE4小鼠系-一个具有低SWR，另一个具有高SWR-CA3 SG 活性，分别指apoE4敏感(apoE4-S)和apoE4抗性(apoE4-R)系-用于研究 载脂蛋白E4的易感性和耐药性的机制S对阿尔茨海默病的不利影响。 在目标1中，我们将从神经生理学的角度对apoE4敏感和抗apoE4品系进行全面的鉴定。 行为和神经病理水平，并探索性别依赖的影响。在目标2中，使用这两行，我们将 从基因组上确定对载脂蛋白E4‘S有害效应的易感或抗性机制 和单核转录水平，并探讨性别依赖的修饰机制。这个 这些研究将有助于阐明载脂蛋白E4‘S在AD发病中的作用机制 并确定治疗或预防与apoE4相关的AD的潜在靶点。