College of Artificial Intelligence, Nanjing Agricultural University, No.1 Weigang Road, Nanjing, Jiangsu, 210095, China; School of Biomedical Informatics, The University of Texas Health Science Center at Houston, 7000 Fannin Street, Houston, TX, 77030, USA.
School of Biomedical Informatics, The University of Texas Health Science Center at Houston, 7000 Fannin Street, Houston, TX, 77030, USA.
Comput Biol Med. 2021 Jun;133:104374. doi: 10.1016/j.compbiomed.2021.104374. Epub 2021 Apr 5.
Alzheimer's disease (AD) is the leading cause of age-related dementia, affecting over 5 million people in the United States. Unfortunately, current therapies are largely palliative and several potential drug candidates have failed in late-stage clinical trials. Studies suggest that microglia-mediated neuroinflammation might be responsible for the failures of various therapies. Microglia contribute to Aβ clearance in the early stage of neurodegeneration and may contribute to AD development at the late stage by releasing pro-inflammatory cytokines. However, the activation profile and phenotypic changes of microglia during the development of AD are poorly understood. To systematically understand the key role of microglia in AD progression and predict the optimal therapeutic strategy in silico, we developed a 3D multi-scale model of AD (MSMAD) by integrating multi-level experimental data, to manipulate the neurodegeneration in a simulated system. Based on our analysis, we revealed that how TREM2-related signal transduction leads to an imbalance in the activation of different microglia phenotypes, thereby promoting AD development. Our MSMAD model also provides an optimal therapeutic strategy for improving the outcome of AD treatment.
阿尔茨海默病（AD）是与年龄相关的痴呆症的主要原因，影响了美国超过 500 万人。不幸的是，目前的治疗方法主要是姑息性的，并且几种潜在的药物候选物在后期临床试验中失败了。研究表明，小胶质细胞介导的神经炎症可能是各种治疗失败的原因。小胶质细胞在神经退行性变的早期有助于清除 Aβ，并通过释放促炎细胞因子在晚期促进 AD 的发展。然而，AD 发展中小胶质细胞的激活谱和表型变化尚不清楚。为了系统地了解小胶质细胞在 AD 进展中的关键作用，并通过计算机模拟预测最佳治疗策略，我们通过整合多层次的实验数据，开发了一种 AD 的 3D 多尺度模型（MSMAD），以在模拟系统中操纵神经退行性变。基于我们的分析，我们揭示了 TREM2 相关信号转导如何导致不同小胶质细胞表型的激活失衡，从而促进 AD 的发展。我们的 MSMAD 模型还为改善 AD 治疗的结果提供了最佳的治疗策略。
