Human stem cell–derived monocytes and microglia‐like cells reveal impaired amyloid plaque clearance upon heterozygous or homozygous loss of TREM2
In: Alzheimer's & Dementia, Jg. 15 (2018), Heft 3, S. 453-464
academicJournal
Zugriff:
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 +/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.
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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
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Autor/in / Beteiligte Person: | Claes, Christel ; Van Den Daele, Johanna ; Boon, Ruben ; Schouteden, Sarah ; Colombo, Alessio ; Monasor, Laura Sebastian ; Fiers, Mark ; Ordovás, Laura ; Nami, Fatemeh ; Arefeh ; Bohrmann, Bernd ; Tahirovic, Sabina ; De Strooper, Bart ; Verfaillie, Catherine M. ; Agentschap voor Innovatie door Wetenschap en Technologie ; European Molecular Biology Organization |
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Zeitschrift: | Alzheimer's & Dementia, Jg. 15 (2018), Heft 3, S. 453-464 |
Veröffentlichung: | Wiley, 2018 |
Medientyp: | academicJournal |
ISSN: | 1552-5260 |
DOI: | 10.1016/j.jalz.2018.09.006 |
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