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

项目摘要 阿尔茨海默病（AD）是痴呆症的最常见形式之一，在过去的十年中， 65岁的人和近一半的85岁以上的人。AD目前是无法治疗的， 关心许多针对AD的尝试治疗靶向淀粉样蛋白β（Ab）斑块，但这些治疗都具有一定的局限性。 在临床试验中失败1，2.新出现的证据表明，tau蛋白病理学可能在发展中发挥因果作用， 的AD。由小胶质细胞引起的炎症可能先于致病性tau 3 -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 代谢重编程，以提供激活所需的能量和底物9，10，和线粒体 功能障碍可能导致AD 11中的异常炎症反应。APOE 4风险等位基因沿着 小胶质细胞Trem 2受体的R47 H变体在增加AD风险方面都显示出较大的效应量。APOE 4是 在大约20%的人群中发现，而R47 H突变则要罕见得多， 1%的人口12。APOE 3等位基因被认为对疾病风险是中性的，通常用作对照 在实验中比较。APOE是Trem 2受体的已知配体，并且Trem 2激活是稳健的。 增加小胶质细胞APOE表达，以及影响细胞代谢和炎症。激活 小胶质细胞Trem 2-APOE通路与高度炎症相关13，14。然而，机械 该途径的基础还没有很好地理解，并且很少有关于相互作用的研究 风险变体R47 H和APOE 4之间的差异。我的初步数据表明，R47 H/+具有显著的差异， 与APOE 4背景相比，对APOE 3背景的影响，使得R47 H与APOE 3（R47 H-E3） R47 H对tau蛋白的反应增强，线粒体呼吸增加，但R47 H与APOE 4 （R47 H-E4）具有低炎症反应和降低的线粒体功能。这种差异化的反应是 伴随R47 H-E3中AKT活化增强，但R47 H-E4中AKT活化降低，表明 这些表型的潜在机制参与。我假设AKT信号的改变驱动了 在E3与E4背景下，R47 H对线粒体呼吸和炎症的不同作用。在这 因此，我的目标是进一步阐明R47 H与不同APOE基因型之间的相互作用，以影响小胶质细胞。 在体外使用原发性小胶质细胞模型和在体内使用tau蛋白病小鼠， 模型然后，我将探索潜在的机制参与AKT在这一途径中使用AKT抑制。 这些研究将为更好地理解疾病相关的功能和机制提供帮助。 Trem 2-APOE通路在小胶质细胞中的作用，为AD的治疗提供了新的靶点。

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.