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Human stem cell–derived monocytes and microglia‐like cells reveal impaired amyloid plaque clearance upon heterozygous or homozygous loss of TREM2
Author(s) -
Claes Christel,
Van Den Daele Johanna,
Boon Ruben,
Schouteden Sarah,
Colombo Alessio,
Monasor Laura Sebastian,
Fiers Mark,
Ordovás Laura,
Nami FatemehArefeh,
Bohrmann Bernd,
Tahirovic Sabina,
De Strooper Bart,
Verfaillie Catherine M.
Publication year - 2019
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2018.09.006
Subject(s) - trem2 , microglia , amyloid (mycology) , cell , phagocytosis , monocyte , stem cell , pathology , microbiology and biotechnology , immunology , medicine , chemistry , biology , inflammation , biochemistry
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 +/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.