Pathological Changes in Alzheimer's Disease Analyzed Using Induced Pluripotent Stem Cell-Derived Human Microglia-Like Cells

Microglia constitute the majority of innate immune cells in the brain, and their dysfunction is associated with various central nervous system diseases. Human microglia are extremely difficult to obtain experimentally, thereby limiting studies on their role in complex diseases. Microglia derived from human stem cells provide new tools to assess the pathogenesis of complex diseases and to develop effective treatment methods. This study aimed to develop a reliable method to derive human microglial-like cells (iMGLs) from induced pluripotent stem cells (iPSCs) expressing microglia-specific markers IBA1 and TMEM119 and respond to lipopolysaccharide (LPS) stimulation. Thereafter, we compared iMGL functions from Alzheimer's disease (AD) patients and cognitive normal controls (CNCs). AD-iMGLs displayed stronger phagocytic ability with or without stimulation. High LPS concentrations (>2 mu g/ml) caused death in CNC-iMGLs, while AD-iMGLs did not display significant cell death. Cytokine analysis revealed that TNE-alpha, IL-6, and IL-10 secreted by AD-iMGLs were significantly increased upon LPS stimulation compared to those in CNC-iMGLs. The present results indicate that AD-iMGLs exhibit significant inflammatory characteristics and can reflect some pathological changes in microglia in AD, thereby providing new valuable tools to screen candidate drugs for AD and to elucidate the mechanisms underlying AD pathogenesis.