A network‐based drug‐screening platform for Alzheimer’s disease by integrating mathematical modeling and pathological features of human brain organoids

Abstract

Background: Developing effective drugs for Alzheimer's disease (AD), the most common cause of dementia, has been difficult because of complicated pathogenesis. The difficulty of acquiring human brain samples and the lack of a disease model that adequately recapitulates the pathological hallmarks pose significant challenges in the field.Method: Here, we report an efficient, network-based drug-screening platform developed by integrating mathematical modelling and the pathological features of AD with human iPSC-derived cerebral organoids (iCOs), including CRISPR-Cas9-edited isogenic lines. We use 1,300 organoids from 11 participants to build a high-content screening (HCS) system and test blood-brain barrier-permeable FDA-approved drugs.Result: Our results confirmed that our iCOs had pathological features of AD, and thus could be an appropriate model reflecting characteristics of the actual disease-related human brain lesions. Also, We completed the construction and validation of the molecular regulatory network model for AD. We proposed candidate drugs based on systems analysis of the dynamical network model with detailed regulatory mechanisms.We found that all of the candidate drugs were effective to some degree in reducing Aβ or tau deposition and enhancing or maintaining neuronal cell viability. Conclusion:Our study provides a strategy for precision medicine through the convergence of mathematical modelling and a miniature pathological brain model using iCOs.With further generation of the iCOs or iPSC-derived microglia (iMG) from various types of AD patients, our approach may propose strategies for the precision medicine therapy.