While genetics highlight the role of microglia in Alzheimer's disease (AD), one third of putative AD-risk genes lack adequate mouse orthologs. Here, we successfully engraft human microglia derived from embryonic stem cells in the mouse brain. The cells recapitulate transcriptionally human primary microglia ex vivo and show expression of human specific AD-risk genes. Oligomeric Amyloid-β induces a divergent response in human vs. mouse microglia. This model can be used to study the role of microglia in neurological diseases.
Introduction: Murine microglia expressing the Alzheimer's disease-linked TREM2 R47H mutation display variable decrease in phagocytosis, while impaired phagocytosis is reported following loss of TREM2. However, no data exist on TREM2 1/R47H human microglia. Therefore, we created human pluripotent stem cell (hPSC) monocytes and transdifferentiated microglia-like cells (tMGs) to examine the effect of the TREM2 1/R47H mutation and loss of TREM2 on phagocytosis. Methods: We generated isogenic TREM2 1/R47H , TREM2 1/2 , and TREM2 2/2 hPSCs using CRISPR/ Cas9. Following differentiation to monocytes and tMGs, we studied the uptake of Escherichia coli fragments and analyzed amyloid plaque clearance from cryosections of APP/PS1 1/2 mouse brains. Results: We demonstrated that tMGs resemble cultured human microglia. TREM2 1/2 and TREM2 2/2 hPSC monocytes and tMGs phagocytosed significantly less E. coli fragments and cleared less amyloid plaques than wild-type hPSC progeny, with no difference for TREM2 1/R47H progeny. Discussion: In vitro phagocytosis of hPSC monocytes and tMGs was not affected by the TREM2 1/R47H mutation but was significantly impaired in TREM2 1/2 and TREM2 2/2 progeny.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.