Trem2-mediated microglia-neuronal axis in Alzheimer disease pathogenesis

Trem2介导的小胶质细胞神经元轴在阿尔茨海默病发病机制中的作用

• 批准号: 10459558
• 负责人: LUCIANO D'ADAMIO
• 金额: $ 78.25万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10459558
• 关键词: Abeta clearance; Adult; Age-associated memory impairment; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Amino Acids; Amyloid Beta A4 Precursor Protein; Amyloid beta-Protein; Animal Model; Animals; Behavioral; Binding; Brain; Brain Pathology; Cells; Cerebrum; Cognitive; Consensus; Dementia; Deposition; Depressed mood; Disease; Elderly; Equilibrium; Family Caregiver; Genetic; Human; Impaired cognition; Impairment; Individual; Intelligence; Knock-in; Lead; Learning; Link; Longevity; Mediating; Memory; Microglia; Microtubules; Modeling; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Organism; Pathogenesis; Pathogenicity; Pathologic; Pathologic Processes; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Physiological Processes; Population; Prevalence; Protein Isoforms; Proteolytic Processing; Rattus; Research; Risk; Rodent; Role; Senile Plaques; Signal Transduction; Societies; Spices; Synaptic Transmission; TNF gene; TREM2 gene; Tauopathies; Testing; Therapeutic; Transgenic Model; Transgenic Organisms; Treatment Efficacy; Variant; amyloid precursor protein processing; autosomal dominant mutation; base; beta secretase; drug testing; early onset; familial Alzheimer disease; gamma secretase; hyperphosphorylated tau; insight; neuroinflammation; overexpression; presenilin-1; presenilin-2; prevent; protective allele; targeted treatment; tau Proteins; tau expression; therapeutic evaluation; therapeutic target; therapeutically effective; transcriptome; transcriptomics

Abstract Alzheimer’s Disease (AD) is the most common cause of ageing-dependent dementia in the world and is associated with cerebral amyloid plaques, mostly composed of Aβ peptides, and intraneuronal neurofibrillary tangles, mostly composed by hyperphosphorylated tau. The impacts of AD on patients, families, caregivers and society are shattering. Regrettably, AD-modifying drugs are unavailable underscoring the scant understanding of AD pathogenesis. ~5% of AD cases have early onset (<65 yo) and are due to Familial autosomal dominant mutations in APP, PSEN1 and PSEN2 (FAD); ~95% of cases are sporadic with late onset (>65 yo, SAD). Yet, commonly used animal organisms model FAD. This may be an issue if FAD and SAD present significant pathogenic differences. If so, therapeutics effective in FAD animals may have limited efficacy in SAD patients. Thus, models that reproduce the pathogenesis of SAD are needed to identify therapeutic targets and test SAD-modifying therapeutics. Variants of the microglia gene TREM2 increase the risk of SAD by 3 fold. To gain insights into the pathogenic mechanisms of SAD, we generated rats carrying the p.R47H pathogenic variant in the rat Trem2 gene (Trem2R47H). Rat and human APP differ by 3 amino acids in the Aβ region. These differences may be crucial in this model organism because: 1) human Aβ possesses higher propensity to form toxic species as compared to rodent Aβ; 2) the pathogenic role of the p.R47H TREM2 variant may be linked to deficits in microglia-mediated human Aβ clearance. To overcome this issue, we humanized the rat Aβ sequence (Apph allele); thus, our rat models produce human Aβ from the endogenous rat App gene. We choose a knock in (KI) approach rather than the more common transgenic overexpression approach because KI models make no preconceived assumption about pathogenic mechanisms, except the unbiased genetic one. In contrast, transgenic models, which produce high levels of Ab and can readily deposit amyloid plaques, are based on the hypothesis that plaques and/or other forms of toxic Ab have a central pathogenic role. We propose to dissect pathogenic mechanisms triggered by the p.R47H pathogenic variant using these KI rat models. We will also study the impact of Trem2R47H on the pathological processes triggered by the Apps and Psen1LF FAD mutations. We will analyze microglia function, cell-to-cell transcriptomic changes in the brain, APP processing, brain pathology, neuro-inflammation and neurodegeneration, synaptic transmission/plasticity, learning & memory. Dissecting pathogenic pathways set off by the Trem2R47H variant may pave the way to therapeutic approaches that can prevent/delay sporadic AD.

摘要：阿尔茨海默病（AD）是导致衰老的最常见原因。 世界上最常见的痴呆症，与大脑淀粉样斑块有关，该斑块主要由 Aβ 组成 肽和神经元内神经原纤维缠结，主要由过度磷酸化组成 头。 AD 对患者、家庭、护理人员和社会的影响是毁灭性的。遗憾的是， AD 缓解药物的缺乏凸显了人们对 AD 发病机制的了解不足。 ~5% 的 AD 病例早发（<65 岁），且由家族性常染色体显性遗传所致 APP、PSEN1 和 PSEN2 (FAD) 突变； ~95% 的病例是散发性的，晚发 (>65 哟，悲伤）。然而，常用的动物模型是FAD。如果 FAD 和 SAD 存在显着的致病差异。如果是这样，对 FAD 动物有效的治疗方法可能 对 SAD 患者的疗效有限。因此，重现 SAD 发病机制的模型是 需要确定治疗靶点并测试 SAD 改善疗法。的变体 小胶质细胞基因 TREM2 会使 SAD 的风险增加 3 倍。为了深入了解致病因素 SAD的机制，我们产生了携带p.R47H致病性变异的大鼠 Trem2 基因（Trem2R47H）。大鼠和人类 APP 的 Aβ 区域有 3 个氨基酸不同。这些 差异在该模型生物中可能至关重要，因为：1) 人类 Aβ 具有更高的 与啮齿动物 Aβ 相比，形成有毒物质的倾向； 2) p.R47H的致病作用 TREM2 变异可能与小胶质细胞介导的人类 Aβ 清除缺陷有关。到 为了克服这个问题，我们将大鼠 Aβ 序列（Apph 等位基因）人源化；因此，我们的大鼠模型 从内源性大鼠 App 基因产生人 Aβ。我们选择敲入（KI）方法 而不是更常见的转基因过度表达方法，因为 KI 模型不产生 关于致病机制的先入为主的假设，除了无偏见的遗传假设。在 相比之下，转基因模型产生高水平的抗体并且可以容易地沉积淀粉样蛋白 斑块，基于斑块和/或其他形式的有毒抗体具有中央的假设 致病作用。我们建议剖析 p.R47H 触发的致病机制 使用这些 KI 大鼠模型研究致病变异。我们还将研究 Trem2R47H 对 Apps 和 Psen1LF FAD 突变触发的病理过程。我们将分析 小胶质细胞功能，大脑中细胞间转录组变化，APP 处理，大脑 病理学、神经炎症和神经变性、突触传递/可塑性、学习 ＆ 记忆。剖析 Trem2R47H 变异引发的致病途径可能会铺平道路 可以预防/延缓散发性 AD 的治疗方法。