Microglia-like cells from patient monocytes demonstrate increased phagocytic activity in probable Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder that is characterized by the accumulation of amyloid plaques, phosphorylated tau tangles and microglia toxicity, resulting in neuronal death and cognitive decline. Since microglia are recognized as one of the key players in the disease, it is crucial to understand how microglia operate in disease conditions and incorporate them into models. The studies on human microglia functions are thought to reflect the post-symptomatic stage of the disease. Recently developed methods involve induced microglia-like cells (iMGs) generated from patients' blood monocytes or induced pluripotent stem cells (iPSCs) as an alternative to studying the microglia cells in vitro. In this research, we aimed to investigate the phenotype and inflammatory responses of iMGs from AD patients. Monocytes derived from blood using density gradient centrifugation were differentiated into iMGs using a cytokine cocktail, including granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-34 (IL-34). After differentiation, cells were assessed by morphological analysis and a microglia surface marker, TMEM119. We used stimulants, lipopolysaccharide (LPS) and beta-amyloid, to examine iMGs' functions. Results showed that iMGs derived from AD patients exhibited increased secretion of pro-inflammatory cytokines upon LPS stimulation. Furthermore, their phagocytic ability was also heightened in stimulated and unstimulated conditions, with cells derived from patients showing increased phagocytic activity compared to healthy controls. Overall, these findings suggest that iMGs derived from patients using the direct conversion method possess characteristics of human microglia, making them an easy and promising model for studying microglia function in AD.