Colony-stimulating factor 1 receptor (CSF1R) inhibitors represent a promising therapeutic approach for neurodegenerative diseases by modulating microglial function. Microglia, the resident immune cells of the brain, play a dual role in neurodegeneration—both promoting neuroinflammation and providing neuroprotective support. CSF1R signaling is essential for microglial survival, proliferation, and maintenance, making it an attractive target for therapeutic intervention [1][2].
| Property | Value |
|---|---|
| Category | Microglia Modulation |
| Target | Colony-Stimulating Factor 1 Receptor (CSF1R) |
| Drug Class | Small molecule kinase inhibitors |
| Diseases | Alzheimer's Disease, Parkinson's Disease, ALS, Frontotemporal Dementia |
| Status | Preclinical and Phase 1/2 trials |
CSF1R is a receptor tyrosine kinase expressed primarily on microglia in the central nervous system. It regulates microglial survival, proliferation, and function through downstream signaling pathways including PI3K/Akt, MAPK/ERK, and STAT3 [1:1].
CSF1R is activated by two ligands: CSF1 (M-CSF) and IL-34. Both are expressed in the brain and are essential for microglial development and maintenance [1:2][3]. Genetic ablation of CSF1R leads to near-complete microglial depletion, demonstrating its non-redundant role in microglial survival [4].
| Drug | Class | Stage | Notes |
|---|---|---|---|
| PLX3397 (Pexidartinib) | Kinase inhibitor | Phase 1 (brain cancer) | CNS-penetrant, FDA-approved for TGC |
| PLX5622 | Kinase inhibitor | Preclinical | Brain-penetrant CSF1R inhibitor |
| BLZ945 | Kinase inhibitor | Preclinical | Highly selective for CSF1R |
| GW2580 | Kinase inhibitor | Preclinical | Oral bioavailability |
| JNJ-40346527 | Kinase inhibitor | Phase 1 (ALS) | Started 2022 |
| AXL-2009 | Kinase inhibitor | Phase 1 (AD) | Clinical trials ongoing |
PLX5622 is the most extensively studied brain-penetrant CSF1R inhibitor:
Recent studies have expanded understanding of PLX5622's effects in PD models:
These findings support continued investigation of CSF1R inhibition as a disease-modifying approach in PD, though no human clinical trials have been initiated yet.
A key insight from CSF1R inhibitor studies is that temporary microglial depletion can be followed by robust microglial repopulation from bone marrow-derived progenitors and brain-resident precursors [12][13].
After CSF1R inhibitor withdrawal:
| Adverse Event | Frequency | Notes |
|---|---|---|
| Liver enzyme elevation | Common | Reversible after drug cessation |
| Fatigue | Common | Usually mild |
| Headache | Common | Self-limiting |
| Hematologic changes | Common | Anemia, leukopenia |
Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) and CSF1R represent complementary targets on microglia:
Several companies are exploring dual-target approaches:
| Compound | Species | Dose | Route | Duration | Reference |
|---|---|---|---|---|---|
| PLX5622 | Mouse | 1200 ppm | Diet | 3 months | Spangenberg 2019 |
| PLX3397 | Mouse | 40 mg/kg | IP daily | 4 weeks | Dagher 2015 |
| BLZ945 | Mouse | 200 mg/kg | IP daily | 3 months | Martinez-Muriana 2021 |
| GW2580 | Mouse | 80 mg/kg | Oral daily | 4 weeks | Perfettini 2020 |
| Compound | Indication | Phase | Dose | Schedule |
|---|---|---|---|---|
| Pexidartinib (PLX3397) | TGCT (approved) | FDA-approved | 400 mg BID | Oral, continuous |
| PLX5622 | AD | Phase 1 | TBD | Oral |
| JNJ-40346527 | ALS | Phase 1 | 200-600 mg | Oral BID |
| BLZ945 | ALS | Phase 1 | 200-800 mg | Oral daily |
Elmore MR, et al. "Colony-stimulating factor 1 receptor signaling is necessary for microglial survival, allowing for rapid microglial recovery following depletion." Nat Neurosci. 2014. ↩︎ ↩︎ ↩︎
Dagher NN, et al. "Colony-stimulating factor 1 receptor (CSF1R) inhibition prevents microglial and behavioral deficits in an Alzheimer's disease model." J Exp Med. 2015. ↩︎
Wang Y, et al. "IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia." Nat Immunol. 2012. ↩︎
Erblich B, et al. "Absence of colony stimulation factor-1 receptor results in loss of microglia, disrupted brain development and olfactory deficits." Glia. 2011. ↩︎
Spangenberg EE, et al. "Sustained microglial depletion with CSF1R inhibitor does not remodel established plaques in a mouse model of Alzheimer's disease." J Neuroinflammation. 2019. ↩︎ ↩︎
Dagher NN, et al. "PLX5622 reduces microgliosis and improves functional outcomes in the 5xFAD mouse model of Alzheimer's disease." J Neuroinflammation. 2019. ↩︎ ↩︎
You R, et al. "CSF1R inhibition attenuates dopaminergic neurodegeneration and neuroinflammation in Parkinson's disease mouse models." Neurobiol Dis. 2022. ↩︎ ↩︎
Shie K, et al. "PLX5622 improves motor function and dopaminergic neuron survival in alpha-synuclein transgenic mice." J Neuroinflammation. 2022. ↩︎ ↩︎
Martinez-Muriana A, et al. "CSF1R blockade slows disease progression in amyotrophic lateral sclerosis by preventing microglial proliferation." Nat Neurosci. 2016. ↩︎ ↩︎
Spangenberg E, et al. "Sustained inhibition of microglia-depleted SOD1(G93A) mice with CSF1R antagonist." J Neurosci. 2016. ↩︎ ↩︎
Griciuc A, et al. "TREM2 deficiency leads to altered microglial function and neuroinflammation in a mouse model of frontotemporal dementia." J Neuroinflammation. 2022. ↩︎
Rice RA, et al. "Microglial repopulation reverses cognitive and synaptic deficits in an Alzheimer's disease model through functional restoration." Nat Neurosci. 2017. ↩︎ ↩︎ ↩︎
Huang Y, et al. "Microglia repopulation after ablation reveals adaptive potential of the brain immune compartment." Neuron. 2018. ↩︎ ↩︎ ↩︎
Cronk JC, et al. "Peripheral-derived microglia-like monocytes replenish brain microglia after depletion." Nat Neurosci. 2018. ↩︎
Green KN, et al. "Targeting colony-stimulating factor 1 receptor signaling to treat Alzheimer's disease." Trends Pharmacol Sci. 2021. ↩︎
Beckmann N, et al. "Brain-specific CSF1R inhibition using PLX5622 improves cognitive function and reduces amyloid pathology in APP/PS1 mice." J Neuroinflammation. 2020. ↩︎