Journal
EMBO JOURNAL
Volume 41, Issue 4, Pages -Publisher
WILEY
DOI: 10.15252/embj.2021109108
Keywords
frontotemporal lobar degeneration; lysosomes; microglia; neurodegeneration; progranulin
Categories
Funding
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [390857198, HA1737/16-1, BR4580/1-1]
- Helmholtz-Gemeinschaft Zukunftsthema Immunology and Inflammation [ZT-0027]
- Alzheimer's Association [ADSF-21-831213-C]
- Vascular Dementia Research Foundation
- BrightFocus Foundation [ADR AD2019604S]
- Hans and Ilse Breuer Foundation
- Alzheimer Forschung Initiative e.V [19063p]
- Projekt DEAL
Ask authors/readers for more resources
Microglial hyperactivation caused by haploinsufficiency of the progranulin encoding gene does not promote neurotoxicity, but rather plays a neuroprotective role. Intervening with the TREM2-dependent microglial state can reduce microglia hyperactivation.
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available