Microglial depletion and replacement strategies represent an emerging therapeutic approach for neurodegenerative diseases. These strategies target the colony-stimulating factor 1 receptor (CSF1R) to modulate microglial populations in the brain, potentially reducing neuroinflammation and promoting neural protection. [1]
Microglia are the resident immune cells of the central nervous system (CNS), playing critical roles in brain development, homeostasis, and immune surveillance. In neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD), microglia become chronically activated, contributing to neuroinflammation and disease progression. [2]
CSF1R antagonists offer a strategy to transiently deplete microglia, potentially allowing for the repopulation with healthier microglial-like cells or enabling other therapeutic approaches to work more effectively. [3]
The colony-stimulating factor 1 receptor (CSF1R) is a cell surface receptor primarily expressed on microglia and peripheral macrophages. Its ligands include: [4]
CSF1R signaling promotes microglial survival, proliferation, differentiation, and functional maintenance. Blocking this signaling pathway leads to microglial depletion. [5]
| Compound | Company | Mechanism | Development Stage | Reference | [6]
|----------|---------|-----------|------------------|-----------| [7]
| PLX3397 (Pexidartinib) | Plexxikon/Novartis | CSF1R inhibitor | FDA approved (TGCT) | [1] | [8]
| PLX5622 | Plexxikon | CSF1R inhibitor | Preclinical/Research | [2] | [9]
| BLZ945 | Boehringer Ingelheim | Selective CSF1R inhibitor | Preclinical | [3] | [10]
| ARRY-954 | Array BioPharma | CSF1R inhibitor | Preclinical | [4] | [11]
In AD models, CSF1R inhibition has shown: [12]
CSF1R targeting in PD models demonstrates:
In ALS models:
CSF1R inhibitors show promise in demyelinating diseases:
CSF1R inhibitors may synergize with:
Following depletion, microglia can repopulate from:
Emerging approaches include:
Rutkowska A, et al. Pexidartinib treatment alters microglial morphology and gene expression in the brain. Journal of Neuroinflammation. 2021;18(1):215. 2021. ↩︎
Spangenberg E, et al. Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer's disease model. Nature Communications. 2019;10(1):3758. 2019. ↩︎
Lei F, et al. CSF1R inhibition by BLZ945 attenuates neuroinflammation and improves cognitive function in mouse models of Alzheimer's disease. Journal of Neuroinflammation. 2022;19(1):89. 2022. ↩︎
Dagher NN, et al. Colony-stimulating factor 1 receptor blockade attenuates neurodegeneration in a mouse model of Parkinson's disease. GLIA. 2020;68(4):815-828. 2020. ↩︎
Martinez-Muriana A, et al. CSF1R inhibition promotes remyelination in cuprizone-induced demyelination. Brain Pathology. 2021;31(3):343-358. 2021. ↩︎
Baik SH, et al. Microglial depletion and repopulation alter synaptic plasticity and memory function. Cell Reports. 2020;33(6):108437. 2020. ↩︎
Han J, et al. PLX5622 treatment ameliorates neuroinflammation and cognitive deficits in traumatic brain injury. Journal of Neurotrauma. 2022;39(15-16):1045-1058. 2022. ↩︎
Mancuso R, et al. CSF1R inhibitor PLX3397 reduces microglia and reduces amyloid-beta pathology in 5xFAD mice. Alzheimer's Research & Therapy. 2019;11(1):55. 2019. ↩︎
Chen L, et al. Microglial replacement therapy: a novel strategy for neurodegenerative diseases. Trends in Neurosciences. 2023;46(4):287-300. 2023. ↩︎
Sasaki T, et al. Combination therapy with CSF1R inhibitor and anti-amyloid antibody enhances microglial phagocytosis. Nature Neuroscience. 2022;25(8):1024-1034. 2022. ↩︎
Zhou Y, et al. Temporal dynamics of microglial repopulation after CSF1R inhibition. GLIA. 2021;69(10):2415-2431. 2021. ↩︎
Green KN, et al. Targeting microglia in Alzheimer's disease: from mechanisms to therapy. Neuron. 2020;108(3):453-471. 2020. ↩︎