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

Claes, Christel; Bohrmann, Bernd; Fiers, Mark; Nami, FatemehArefeh; Schouteden, Sarah; Ordovás, Laura; Boon, Ruben; Sebastian Monasor, Laura; De Strooper, Bart; Tahirovic, Sabina; Colombo, Alessio; Van Den Daele, Johanna; Verfaillie, Catherine M

doi:10.1016/j.jalz.2018.09.006

Journal Article

DZNE-2020-06856

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

Claes, C. ; Van Den Daele, J. ; Boon, R. ; Schouteden, S. ; Colombo, A.DZNE* ; Sebastian Monasor, L.DZNE* ; Fiers, M. ; Ordovás, L. ; Nami, F. ; Bohrmann, B. ; Tahirovic, S.DZNE* ; De Strooper, B. ; Verfaillie, C. M. (Corresponding author)

2019
Elsevier Amsterdam [u.a.]

Alzheimer's and dementia 15(3), 453-464 (2019) [10.1016/j.jalz.2018.09.006]

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Please use a persistent id in citations: doi:10.1016/j.jalz.2018.09.006

Abstract: 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.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.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.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.

Keyword(s): Amyloid beta-Protein Precursor: genetics (MeSH) ; Amyloid beta-Protein Precursor: metabolism (MeSH) ; Animals (MeSH) ; Brain (MeSH) ; CRISPR-Cas Systems (MeSH) ; Cells, Cultured (MeSH) ; Escherichia coli (MeSH) ; Membrane Glycoproteins: deficiency (MeSH) ; Membrane Glycoproteins: genetics (MeSH) ; Mice, Transgenic (MeSH) ; Microglia: metabolism (MeSH) ; Monocytes: metabolism (MeSH) ; Phagocytosis (MeSH) ; Plaque, Amyloid: metabolism (MeSH) ; Pluripotent Stem Cells (MeSH) ; Presenilin-1: genetics (MeSH) ; Presenilin-1: metabolism (MeSH) ; Receptors, Immunologic: deficiency (MeSH) ; Receptors, Immunologic: genetics (MeSH)