TY  - JOUR
AU  - Reifschneider, Anika
AU  - Robinson, Sophie
AU  - van Lengerich, Bettina
AU  - Gnoerich, Johannes
AU  - Logan, Todd
AU  - Heindl, Steffanie
AU  - Vogt, Miriam A
AU  - Weidinger, Endy
AU  - Riedl, Lina
AU  - Wind, Karin
AU  - Zatcepin, Artem
AU  - Pesämaa, Ida
AU  - Haberl, Sophie
AU  - Nuscher, Brigitte
AU  - Kleinberger, Gernot
AU  - Klimmt, Julien
AU  - Götzl, Julia K
AU  - Liesz, Arthur
AU  - Bürger, Katharina
AU  - Brendel, Matthias
AU  - Levin, Johannes
AU  - Diehl-Schmid, Janine
AU  - Suh, Jung
AU  - Di Paolo, Gilbert
AU  - Lewcock, Joseph W
AU  - Monroe, Kathryn M
AU  - Paquet, Dominik
AU  - Capell, Anja
AU  - Haass, Christian
TI  - Loss of TREM2 rescues hyperactivation of microglia, but not lysosomal deficits and neurotoxicity in models of progranulin deficiency.
JO  - The EMBO journal
VL  - 41
IS  - 4
SN  - 1460-2075
CY  - Hoboken, NJ [u.a.]
PB  - Wiley
M1  - DZNE-2022-00231
SP  - e109108
PY  - 2022
N1  - (CC BY-NC-ND)
AB  - Haploinsufficiency of the progranulin (PGRN)-encoding gene (GRN) causes frontotemporal lobar degeneration (GRN-FTLD) and results in microglial hyperactivation, TREM2 activation, lysosomal dysfunction, and TDP-43 deposition. To understand the contribution of microglial hyperactivation to pathology, we used genetic and pharmacological approaches to suppress TREM2-dependent transition of microglia from a homeostatic to a disease-associated state. Trem2 deficiency in Grn KO mice reduced microglia hyperactivation. To explore antibody-mediated pharmacological modulation of TREM2-dependent microglial states, we identified antagonistic TREM2 antibodies. Treatment of macrophages from GRN-FTLD patients with these antibodies led to reduced TREM2 signaling due to its enhanced shedding. Furthermore, TREM2 antibody-treated PGRN-deficient microglia derived from human-induced pluripotent stem cells showed reduced microglial hyperactivation, TREM2 signaling, and phagocytic activity, but lysosomal dysfunction was not rescued. Similarly, lysosomal dysfunction, lipid dysregulation, and glucose hypometabolism of Grn KO mice were not rescued by TREM2 ablation. Synaptic loss and neurofilament light-chain (NfL) levels, a biomarker for neurodegeneration, were further elevated in the Grn/Trem2 KO cerebrospinal fluid (CSF). These findings suggest that TREM2-dependent microglia hyperactivation in models of GRN deficiency does not promote neurotoxicity, but rather neuroprotection.
KW  - Animals
KW  - Antibodies: immunology
KW  - Antibodies: pharmacology
KW  - Brain: diagnostic imaging
KW  - Brain: physiopathology
KW  - Disease Models, Animal
KW  - Female
KW  - Frontotemporal Lobar Degeneration: metabolism
KW  - Frontotemporal Lobar Degeneration: pathology
KW  - Humans
KW  - Lysosomes: metabolism
KW  - Lysosomes: pathology
KW  - Male
KW  - Membrane Glycoproteins: genetics
KW  - Membrane Glycoproteins: immunology
KW  - Membrane Glycoproteins: metabolism
KW  - Mice, Inbred C57BL
KW  - Mice, Knockout
KW  - Microglia: drug effects
KW  - Microglia: physiology
KW  - Monocytes: drug effects
KW  - Monocytes: metabolism
KW  - Progranulins: deficiency
KW  - Receptors, Immunologic: genetics
KW  - Receptors, Immunologic: immunology
KW  - Receptors, Immunologic: metabolism
KW  - Syk Kinase: metabolism
KW  - frontotemporal lobar degeneration (Other)
KW  - lysosomes (Other)
KW  - microglia (Other)
KW  - neurodegeneration (Other)
KW  - progranulin (Other)
KW  - Antibodies (NLM Chemicals)
KW  - Grn protein, mouse (NLM Chemicals)
KW  - Membrane Glycoproteins (NLM Chemicals)
KW  - Progranulins (NLM Chemicals)
KW  - Receptors, Immunologic (NLM Chemicals)
KW  - TREM2 protein, human (NLM Chemicals)
KW  - Trem2 protein, mouse (NLM Chemicals)
KW  - SYK protein, human (NLM Chemicals)
KW  - Syk Kinase (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:35019161
C2  - pmc:PMC8844989
DO  - DOI:10.15252/embj.2021109108
UR  - https://pub.dzne.de/record/163471
ER  -