Human stem cell–derived monocytes and microglia‐like cells reveal impaired amyloid plaque clearance upon heterozygous or homozygous loss of TREM2.

Introduction: Murine microglia expressing the Alzheimer's disease–linked TREM2R47H mutation display variable decrease in phagocytosis, while impaired phagocytosis is reported following loss of TREM2. However, no data exist on TREM2+/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+/R47H mutation and loss of TREM2 on phagocytosis. Methods: We generated isogenic TREM2+/R47H, TREM2+/−, and TREM2−/− 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+/− mouse brains. Results: We demonstrated that tMGs resemble cultured human microglia. TREM2+/− and TREM2−/− 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+/R47H progeny. Discussion: In vitro phagocytosis of hPSC monocytes and tMGs was not affected by the TREM2+/R47H mutation but was significantly impaired in TREM2+/− and TREM2−/− progeny. [ABSTRACT FROM AUTHOR]

Copyright of Alzheimer's & Dementia: The Journal of the Alzheimer's Association is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)