scholarly journals CSF1R inhibition rescues tau pathology and neurodegeneration in an A/T/N model with combined AD pathologies, while preserving plaque associated microglia

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Chritica Lodder ◽  
Isabelle Scheyltjens ◽  
Ilie Cosmin Stancu ◽  
Pablo Botella Lucena ◽  
Manuel Gutiérrez de Ravé ◽  
...  
Keyword(s):  
Neurofibrillary Tangles ◽  
Microglial Activation ◽  
Amyloid Plaques ◽  
Colony Stimulating Factor ◽  
Tau Pathology ◽  
Preclinical Models ◽  
Receptor Inhibition ◽  
Single Cell Rna Sequencing ◽  
The Brain ◽  
Stimulating Factor

AbstractAlzheimer's disease (AD) is characterized by a sequential progression of amyloid plaques (A), neurofibrillary tangles (T) and neurodegeneration (N), constituting ATN pathology. While microglia are considered key contributors to AD pathogenesis, their contribution in the combined presence of ATN pathologies remains incompletely understood. As sensors of the brain microenvironment, microglial phenotypes and contributions are importantly defined by the pathologies in the brain, indicating the need for their analysis in preclinical models that recapitulate combined ATN pathologies, besides their role in A and T models only. Here, we report a new tau-seed model in which amyloid pathology facilitates bilateral tau propagation associated with brain atrophy, thereby recapitulating robust ATN pathology. Single-cell RNA sequencing revealed that ATN pathology exacerbated microglial activation towards disease-associated microglia states, with a significant upregulation of Apoe as compared to amyloid-only models (A). Importantly, Colony-Stimulating Factor 1 Receptor inhibition preferentially eliminated non-plaque-associated versus plaque associated microglia. The preferential depletion of non-plaque-associated microglia significantly attenuated tau pathology and neuronal atrophy, indicating their detrimental role during ATN progression. Together, our data reveal the intricacies of microglial activation and their contributions to pathology in a model that recapitulates the combined ATN pathologies of AD. Our data may provide a basis for microglia-targeting therapies selectively targeting detrimental microglial populations, while conserving protective populations.

scholarly journals Colony stimulating factor 1 receptor inhibition eliminates microglia and attenuates brain injury after intracerebral hemorrhage

2016 ◽  
Vol 37 (7) ◽  
pp. 2383-2395 ◽  
Author(s):  
Minshu Li ◽  
Zhiguo Li ◽  
Honglei Ren ◽  
Wei-Na Jin ◽  
Kristofer Wood ◽  
...  
Keyword(s):  
Intracerebral Hemorrhage ◽  
Autologous Blood ◽  
Lesion Size ◽  
Experimental Models ◽  
Colony Stimulating Factor ◽  
Receptor Inhibition ◽  
Experimental Mouse ◽  
The Brain ◽  
Stimulating Factor ◽  
Blood Brain Barrier Integrity

Microglia are the first responders to intracerebral hemorrhage, but their precise role in intracerebral hemorrhage remains to be defined. Microglia are the only type of brain cells expressing the colony-stimulating factor 1 receptor, a key regulator for myeloid lineage cells. Here, we determined the effects of a colony-stimulating factor 1 receptor inhibitor (PLX3397) on microglia and the outcome in the context of experimental mouse intracerebral hemorrhage. We show that PLX3397 effectively depleted microglia, and the depletion of microglia was sustained after intracerebral hemorrhage. Importantly, colony-stimulating factor 1 receptor inhibition attenuated neurodeficits and brain edema in two experimental models of intracerebral hemorrhage induced by injection of collagenase or autologous blood. The benefit of colony-stimulating factor 1 receptor inhibition was associated with reduced leukocyte infiltration in the brain and improved blood–brain barrier integrity after intracerebral hemorrhage, and each observation was independent of lesion size or hematoma volume. These results demonstrate that suppression of colony-stimulating factor 1 receptor signaling ablates microglia and confers protection after intracerebral hemorrhage.

Dynamic changes in glioma macrophage populations after radiotherapy reveal CSF-1R inhibition as a strategy to overcome resistance

2020 ◽  
Vol 12 (552) ◽  
pp. eaaw7843 ◽  
Author(s):  
Leila Akkari ◽  
Robert L. Bowman ◽  
Jeremy Tessier ◽  
Florian Klemm ◽  
Shanna M. Handgraaf ◽  
...  
Keyword(s):  
Gene Expression ◽  
Standard Of Care ◽  
Colony Stimulating Factor ◽  
Preclinical Models ◽  
Dynamic Changes ◽  
Altered Expression ◽  
Standard Of Care Treatment ◽  
Specific Stage ◽  
Macrophage Populations ◽  
Stimulating Factor

Tumor-associated macrophages (TAMs) and microglia (MG) are potent regulators of glioma development and progression. However, the dynamic alterations of distinct TAM populations during the course of therapeutic intervention, response, and recurrence have not yet been fully explored. Here, we investigated how radiotherapy changes the relative abundance and phenotypes of brain-resident MG and peripherally recruited monocyte-derived macrophages (MDMs) in glioblastoma. We identified radiation-specific, stage-dependent MG and MDM gene expression signatures in murine gliomas and confirmed altered expression of several genes and proteins in recurrent human glioblastoma. We found that targeting these TAM populations using a colony-stimulating factor–1 receptor (CSF-1R) inhibitor combined with radiotherapy substantially enhanced survival in preclinical models. Our findings reveal the dynamics and plasticity of distinct macrophage populations in the irradiated tumor microenvironment, which has translational relevance for enhancing the efficacy of standard-of-care treatment in gliomas.

BLZ945 derivatives for PET imaging of colony stimulating factor-1 receptors in the brain

2021 ◽  
Author(s):  
Berend van der Wildt ◽  
Zheng Miao ◽  
Samantha T. Reyes ◽  
Jun H. Park ◽  
Jessica L. Klockow ◽  
...  
Keyword(s):  
Pet Imaging ◽  
Colony Stimulating Factor ◽  
The Brain ◽  
Stimulating Factor

Granulocyte colony-stimulating factor potential use in the treatment of children with cerebral palsy

2017 ◽  
Vol 7 (1) ◽  
pp. 0-0
Author(s):  
G. Paszko-Patej ◽  
D. Sienkiewicz ◽  
B. Okurowska-Zawada ◽  
W. Kułak
Keyword(s):  
Cerebral Palsy ◽  
Tissue Repair ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Neuroprotective Actions ◽  
Apoptosis And Inflammation ◽  
Brain And Spinal Cord ◽  
The Brain ◽  
Stimulating Factor ◽  
Potential Use

Granulocyte colony-stimulating factor (G-CSF) is a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the blood. Recent studies demonstrated the presence of CSF-receptor (G-CSFR) system in the brain and spinal cord, and their roles in neuroprotection and neural tissue repair, as well as improvement in functional recovery. G-CSF exerts neuroprotective actions through the inhibition of apoptosis and inflammation, and the stimulation of neurogenesis. This review highlights recent studies on the potential use of G-CSF in cerebral palsy.

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