Opposite microglial activation stages upon loss of PGRN or TREM2 result in reduced cerebral glucose metabolism
Abstract
Synopsis

Introduction
Results
Opposite molecular signatures of microglia in Grn−/− and Trem2−/− mice

Confirmation of molecular microglial signatures on protein level

Increased phagocytic capacity, chemotaxis, and clustering around amyloid plaques upon loss of PGRN


Increased TSPO‐PET signals in Grn−/− mice and a human patient with GRN haploinsufficiency

Cerebral hypometabolism upon loss of PGRN and TREM2

Discussion

Materials and Methods
Animal experiments
Gene expression profiling
Data normalization and analysis
sTREM2 ELISA analysis of mouse plasma and brain samples
Cell culture and CRISPR/Cas9 genome editing in BV2 cells
Quantitative real‐time PCR (qRT–PCR)
Isolation of adult primary microglia for immunoblotting
Cell lysis and immunoblotting
Phagocytosis assay
Ex vivo migration assay
Immunohistochemistry and image analysis
Rodent μPET
Patient identification, genetic studies, PGRN ELISA, and PET
Statistical analysis
Data availability
Author contributions
The paper explained
Problem
Results
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Caption: The image shows invasive glioblastoma cells (red), which use blood capillaries (green) to colonize the murine brain parenchyma (DAPI, blue). The invasive cells disseminating from the primary tumour and generating secondary masses form the major obstacle in the therapeutic management of gliomas. Silencing of a fatty acid binding protein (MDGI/FABP3) or treatment with the cationic amphiphilic antihistamine (clemastine) induced death of patient‐derived glioblastoma cells in vitro. MDGI/FABP3 silencing resulted in significant alterations in the lipid composition of lysosomal membranes due to impaired trafficking of polyunsaturated fatty acids into cells, revealing a novel mechanism for MDGI/FABP3 in the maintenance of lysosomal integrity. In addition, clemastine‐treatment resulted in eradication of the invasive glioblastoma cells and prolonged the life‐span of patient‐derived glioblastoma‐bearing mice, supporting the repurposing of clemastine to treat invasive brain tumours. Vadim Le Joncour, Pauliina Filppu, Pirjo Laakkonen, and colleagues: Vulnerability of invasive glioblastoma cells to lysosomal membrane destabilisation. Scientific image by Vadim Le Joncour, Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
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