Studying NF-κB signaling during neuroinflammation in Alzheimer’s Diseases in vitro using hiPSC-derived brain models

• Published in: The Journal of immunology (1950) Vol. 210; no. 1_Supplement; pp. 234 - 234.02
• Main Authors: Songkiatisak, Preeyaporn, Aqdas, Mohammad, Md Toufiqur Rahman, Shah, Oh, Kyu-Seon, Sung, Myong-Hee
• Format: Journal Article
• Language: English
• Published: 01.05.2023
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.210.Supp.234.02

Abstract Neuroinflammation is a key pathological driver of various neurological diseases, including Alzheimer’s disease (AD). NF-κB signaling pathway is widely recognized as a hallmark of inflammation and cellular senescence in which aged microglia may undergo cellular senescence partly influenced by NF-κB. Our previous data indicated that ex vivo microglia comprised of two distinct subpopulations distinguished by morphology and motility. Most microglia cells formed a tight cell cluster, termed “clustered microglia”. The rest was a subpopulation of microglia with smaller cell size and high motility, termed “free-roaming microglia”. In microglia from aged animals, the composition of clustered versus free-roaming subsets was shifted toward a higher prevalence of free-roaming microglia where c-Rel is expressed and the canonical NF-κB signaling is more sustained. To study NF-κB signaling in the context of neuroinflammation, we are developing 3D models, using hiPSC neurons derived from healthy donors of various age groups and co-culturing them with primary microglia from knock-in mice in which their endogenous c-Rel was labeled with a fluorescent protein. Moreover, individuals with APOE-e4 genotype have an increased risk of developing AD. To develop 3D brain models for AD, we will use co-culture of microglia and neurons derived from hiPSCs of APOE-e4 carriers. Live cell imaging and biomarker assessment of microglia and neurons activated by Amyloid β (1–42) will uncover important molecular mechanisms associated with age-dependent interactions between neurons from healthy versus AD-risk individuals, and resident macrophages of the young and aged brains.