Modeling Alzheimer's Disease Using Cortical Organoids Derived from Human Induced Pluriptotent Stem Cells

Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders and causes cognitive impairment and memory deficits of the patients. The mechanism of AD is not well known, due to lack of human brain models. Recently, the novel neural tissue patterning technology has been developed using human induced pluripotent stem cells (hiPSCs) to derive mini-brain tissues called organoids for modeling human brain development and neurological diseases. Thus, the objective of this research is to establish a novel in vitro AD model using 3-D forebrain cortical organoids derived from hiPSCs to study the response to the drug treatment. It is hypothesized that the 3-D forebrain organoids derived from hiPSCs with AD-associated genetic background may partially recapitulate the age-related disease pathology. To test this hypothesis, AD-patient derived hiPSCs with presenilin-1 mutation were used for cortical organoid generation. AD-induced inflammatory responses, matrix remodeling and drug testing were investigated. The results indicate that the cortical organoids derived from AD-associated hiPSCs exhibit a high level of Aβ42 comparing with healthy control. In addition, the AD-derived organoids result in an elevated expression of pro-inflammatory cytokines including IL-6 and TNF-α and alter matrix remodeling protein expression. Our study demonstrates the capacity of hiPSC-derived organoids for modeling AD using neural patterning technology and provides a potential approach for AD-related drug screening.