Trem2-APOE Pathway in Alzheimer's Disease: Exploring the differential effects of R47H on the APOE3 and APOE4 backgrounds in a tauopathy model

阿尔茨海默病中的 Trem2-APOE 通路：探索 R47H 对 tau 蛋白病模型中 APOE3 和 APOE4 背景的不同影响

• 批准号: 10710179
• 负责人: Gillian Kirova Carling
• 金额: $ 4.77万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-18 至 2025-08-17
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10710179
• 关键词: AKT inhibition; Acceleration; Affect; Affinity; Age; Alleles; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid beta-Protein; Automobile Driving; Biomass; Clinical Trials; Data; Dementia; Development; Disease; Disease Progression; Genetic Risk; Genotype; Health; Impaired cognition; Impairment; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Ligands; Link; Lipoproteins; Measures; Memory impairment; Metabolic; Metabolism; Microglia; Mitochondria; Modeling; Mus; Mutation; Nerve Degeneration; Neurofibrillary Tangles; Onset of illness; Pathogenesis; Pathology; Pathway interactions; Persons; Phenotype; Phosphotransferases; Play; Population; Production; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Research; Respiration; Risk Factors; Role; Senile Plaques; Signal Transduction; Synaptophysin; TREM2 gene; Tauopathies; Therapeutic Effect; Toxic effect; Variant; apolipoprotein E-3; apolipoprotein E-4; cognitive function; disorder risk; experimental study; functional outcomes; gene interaction; genetic risk factor; human old age (65+); improved; in vivo; metabolomics; mitochondrial dysfunction; mouse model; neuroinflammation; new therapeutic target; novel; receptor; response; risk variant; tau Proteins; tau mutation; transcriptomics

Project Summary Alzheimer’s disease (AD) is one of the most common forms of dementia, affecting one in ten people over the age of 65 and nearly half of people over the age of 85. AD is currently untreatable, posing a significant health concern. Many attempted treatments for AD target amyloid-beta (Ab) plaques, but these treatments have all failed in clinical trials1,2. Emerging evidence shows that tau pathology may play a causal role in the development of AD. Inflammation prompted by microglia may precede the spread of pathogenic tau3-6, and most AD risk genes are found in microglia, supporting a significant role for inflammation in disease7,8. Inflammation requires metabolic reprogramming to provide the energy and substrates needed for activation9,10, and mitochondrial dysfunction could contribute to aberrant inflammatory responses in AD11. The APOE4 risk allele along with the R47H variant of the microglial Trem2 receptor both display large effect sizes in increasing AD risk. APOE4 is found in approximately 20% of the population, whereas the R47H mutation is much rarer, representing less than 1% of the population12. The APOE3 allele is considered neutral to disease risk and is often used as a control comparison in experiments. APOE is a known ligand of the Trem2 receptor, and Trem2 activation robustly increases microglial APOE expression, as well as affecting cellular metabolism and inflammation. Activation of the microglial Trem2-APOE pathway is associated with heightened inflammation13,14. However, the mechanistic underpinnings of the pathway are not well understood, and there has been little research on the interactions between risk variants R47H and APOE4. My preliminary data indicates that R47H/+ has a remarkable differential effect on the APOE3 background compared to the APOE4 background, such that R47H with APOE3 (R47H-E3) has heightened inflammation in response to tau and increased mitochondrial respiration, but R47H with APOE4 (R47H-E4) has low inflammatory response and decreased mitochondrial function. This differential response is accompanied by enhanced AKT activation in R47H-E3 but reduced AKT activation in R47H-E4, suggesting potential mechanistic involvement in these phenotypes. I hypothesize that alterations in AKT signaling drive the differential effects of R47H on mitochondrial respiration and inflammation in the E3 vs. E4 background. In this proposal, I aim to further elucidate the interactions of R47H with different APOE genotypes to affect microglial metabolism and inflammation, both in vitro using a primary microglia model and in vivo using a tauopathy mouse model. I will then explore the potential mechanistic involvement of AKT in this pathway using AKT inhibition. These studies will provide a better understanding of the function and mechanisms of the disease-implicated Trem2-APOE pathway in microglia, providing novel targets for the treatment of AD.

项目摘要 阿尔茨海默病(AD)是痴呆症最常见的形式之一，每年有十分之一的人受到影响 65岁和近一半的85岁以上的人。AD目前无法治愈，对健康构成重大威胁 担忧。许多针对AD靶向淀粉样β蛋白(Ab)斑块的治疗尝试，但这些治疗方法都 临床试验失败1，2.新出现的证据表明tau病理可能在疾病的发展中起到因果作用 公元一代的。小胶质细胞引发的炎症可能先于致病的tau3-6和大多数AD风险基因的传播 在小胶质细胞中发现，支持炎症在疾病中的重要作用7，8。炎症需要 代谢重新编程以提供激活9，10和线粒体所需的能量和底物 功能障碍可能导致AD11的异常炎症反应。载脂蛋白4风险等位基因与 小胶质细胞TREM2受体的R47H变异在增加AD风险方面都显示出较大的效应大小。载脂蛋白E4是 在大约20%的人群中发现，而R47H突变要罕见得多，代表着不到 人口的1%。APOE3等位基因被认为对疾病风险是中性的，经常被用作对照 在实验中比较。APOE是已知的TREM2受体的配体，TREM2的激活非常强健 增加小胶质细胞载脂蛋白E的表达，并影响细胞代谢和炎症。激活 小胶质细胞TREM2-APOE通路与炎症加剧有关13，14。然而，其机制 这条途径的基础还不是很清楚，关于相互作用的研究也很少 在风险变异体R47H和APOE4之间。我的初步数据显示，R47H/+具有显著的差异 对APOE3背景和APOE4背景的影响，例如R47H与APOE3(R47H-E3) 对tau的反应加剧了炎症，并增加了线粒体呼吸，但R47H与APOE4有关 (R47H-E4)具有低炎症反应和线粒体功能降低的特点。这种不同的反应是 伴有R47H-E3的AKT活性增强，但R47H-E4的AKT活性降低，提示 这些表型中潜在的机械性参与。我假设AKT信号的改变推动了 R47H在E3和E4背景下对线粒体呼吸和炎症的不同影响。在这 建议，我的目的是进一步阐明R47H与不同APOE基因型之间的相互作用，以影响小胶质细胞 代谢和炎症，在体外使用初级小胶质细胞模型，在体内使用坐骨神经病变小鼠 模特。然后，我将利用AKT抑制来探索AKT在这一途径中的潜在机制参与。 这些研究将为更好地了解与疾病有关的疾病的功能和机制提供帮助 小胶质细胞中的TREM2-APOE通路，为AD的治疗提供了新的靶点。