Multi-scale modeling for systematically understanding the key roles of microglia in AD development

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 A beta 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.