Colony-stimulating factor 1 receptor inhibition prevents microglial plaque association and improves cognition in 3xTg-AD mice
Open accessAbstract
BACKGROUND: Microglia are dependent upon colony-stimulating factor 1 receptor (CSF1R) signaling for their survival in the adult brain, with administration of the dual CSF1R/c-kit inhibitor PLX3397 leading to the near-complete elimination of all microglia brainwide. Here, we determined the dose-dependent effects of a specific CSF1R inhibitor (PLX5622) on microglia in both wild-type and the 3xTg-AD mouse model of Alzheimer's disease. METHODS: Wild-type mice were treated with PLX5622 for up to 21 days, and the effects on microglial numbers were assessed. 3xTg-AD mice were treated with PLX5622 for 6 or 12 weeks and effects on microglial numbers and pathology subsequently assessed. RESULTS: High doses of CSF1R inhibitor eliminate most microglia from the brain, but a 75% lower-dose results in sustained elimination of ~30 of microglia in both wild-type and 3xTg-AD mice. No behavioral or cognitive deficits were found in mice either depleted of microglia or treated with lower CSF1R inhibitor concentrations. Aged 3xTg-AD mice treated for 6 or 12 weeks with lower levels of PLX5622 resulted in improved learning and memory. Aβ levels and plaque loads were not altered, but microglia in treated mice no longer associated with plaques, revealing a role for the CSF1R in the microglial reaction to plaques, as well as in mediating cognitive deficits. CONCLUSIONS: We find that inhibition of CSF1R alone is sufficient to eliminate microglia and that sustained microglial elimination is concentration-dependent. Inhibition of the CSF1R at lower levels in 3xTg-AD mice prevents microglial association with plaques and improves cognition.
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In mouse models of AD, genetic or pharmacological depletion of microglia prevented microglia association with amyloid plaques and neuronal loss, leading to improved learning and memory without affecting amyloid plaque load.
“In mouse models of AD genetic or pharmacological depletion of microglia prevented microglia association with amyloid plaques and neuronal loss, which led to improved learning and memory without affecting amyloid plaque load in mouse brain (Dagher et al., 2015; Rice et al., 2015; Spangenberg et al., 2016).”
From Alzheimer's-associated PU.1 expression levels regulate microglial inflammatory response (2021) · cites this paper as Dagher et al., 2015
The Results and Discussion report that pharmacological CSF1R inhibition in aged 3xTg-AD mice reduced microglial association with plaques and improved learning and memory without changing Aβ levels or plaque load. This paper does not report that its treatment prevented neuronal loss, and its AD-mouse experiment used pharmacological inhibition rather than genetic depletion. The indexed passages have section labels but no page numbers. (LLM, conf=0.87)
Experimental — accuracy not yet measuredCXCL1, CCL5, LIF, and CSF1 regulate microglia activation, survival, and migration to the site of injury.
“Notably, CXCL1, CCL5, LIF, and CSF1 regulate microglia activation, survival, and migration to the site of injury [169–172]”
From Oligodendrocyte death and myelin loss in the cuprizone model: an updated overview of the intrinsic and extrinsic causes of cuprizone demyelination (2022) · cites this paper as [171]
The Discussion (page unavailable) identifies CSF1 as a CSF1R ligand and reports that microglia require CSF1R signaling for survival. The Results (page unavailable) show that CSF1R inhibition reduces microglial migration toward Aβ-stimulated media. The paper does not establish that CXCL1, CCL5, or LIF regulate these functions, or that the named factors direct migration to a site of injury. (LLM, conf=0.86)
Experimental — accuracy not yet measuredStage 2 DAMs are essential early in AD but may become dysregulated and ultimately detrimental later in disease progression.
“Although Stage 2 DAMs are essential early in AD, they may become dysregulated and ultimately detrimental later in disease progression.44–46”
From TET2-mutant myeloid cells mitigate Alzheimer’s disease progression via CNS infiltration and enhanced phagocytosis in mice (2025) · cites this paper as [46]
The Discussion (page unavailable) suggests that microglial association with Aβ deposits may be protective early in AD, while preventing that association may be beneficial later. The Introduction (page unavailable) also describes an initially beneficial microglial response that can become chronically inflammatory and damaging. Neither passage identifies Stage 2 DAMs specifically, and the Discussion presents early protection as a possibility rather than establishing that those cells are essential. (LLM, conf=0.87)
Experimental — accuracy not yet measuredSeveral groups have reported that microglial elimination via CSF1R inhibition improves behavioral performance and synaptic functioning independent of Aβ accumulation in multiple transgenic mouse models of AD (3xTg, 5xFAD, APP/PS1).
“While the use of these agents is limited in experimental TBI studies, several groups have reported that microglial elimination [via colony-stimulating factor 1 receptor (CSF1R) inhibition] improves behavioral performance and synaptic functioning independent of Aβ accumulation in multiple transgenic mouse models of AD (3xTg, 5xFAD, APP/PS1) (236–238).”
From The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease (2018) · cites this paper as [238]
The Abstract Results and Results section report improved learning and memory in CSF1R-inhibitor-treated 3xTg-AD mice, with unchanged Aβ levels and plaque loads. This paper does not report improved synaptic functioning; it studies 3xTg-AD mice, while the sentence’s other model-specific findings may be covered by its other citations. (LLM, conf=0.87)
Experimental — accuracy not yet measuredIl34 and Csf1 are soluble factors that bind Csf1r and are necessary for microglial development and maintenance in vivo.
“expression of Il34 and Csf1, soluble factors that bind to Csf1r and required for microglial development and maintenance in vivo49”
From A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease (2017) · cites this paper as [49]
Microglia require CSF1 receptor signaling for ongoing survival, and in the CNS, CSF1R is restricted to microglia.
“Microglia require CSF1 receptor (CSF1R) signaling for ongoing survival [171, 172] (Fig. 4I) and in the CNS, CSF1R is restricted to microglia [203].”
From Oligodendrocyte death and myelin loss in the cuprizone model: an updated overview of the intrinsic and extrinsic causes of cuprizone demyelination (2022) · cites this paper as [171]
A pharmacological method based on CSF1R inhibition can eliminate virtually all (>99%) microglia from the murine brain for several months.
“Previously, we developed a pharmacological method to eliminate virtually all ( 99%) microglia from the murine brain for several months at a time (Elmore et al. , 2014; Dagher et al. , 2015), based on inhibition of colony-stimulating factor 1 receptor (CSF1Ri).”
From Microglial depletion prevents extracellular matrix changes and striatal volume reduction in a model of Huntington's disease (2020) · cites this paper as Dagher et al., 2015
Microglial CSF1R signalling is essential for their survival and has become a thoroughly tested and highly replicated model for targeted elimination of microglia.
“Microglial CSF1R signalling is essential to their survival and has become a thoroughly tested and highly replicated model for targeted elimination of microglia (Elmore et al. , 2014; Asai et al. , 2015; Dagher et al. , 2015; Rice et al. , 2015; Acharya et al. , 2016; Feng et al. , 2016; Spangenberg et al. , 2016; Stafford et al. , 2016; Szalay et al. , 2016; Li et al. , 2017; Bennett et al. , 2018”
From Microglial depletion prevents extracellular matrix changes and striatal volume reduction in a model of Huntington's disease (2020) · cites this paper as Dagher et al., 2015
The absence of microglia did not significantly alter the levels of Aβ38, Aβ40, or Aβ42 in detergent-soluble or -insoluble cortical and thalamic homogenates in either the 4- or 7-month cohorts.
“The absence of microglia did not significantly alter the levels of Aβ38, Aβ40, or Aβ42, in detergent-soluble or -insoluble cortical and thalamic homogenates in either the 4- or 7- month cohorts (Fig. 5a–h), in line with multiple studies showing that CSF1R inhibition does not affect Aβ production/clearance10,27,28.”
From Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model (2019) · cites this paper as [27]
Treatment with PLX5622 prevented association of microglia with plaques and improved cognition in the 3xTg-AD mouse model of Alzheimer disease.
“Treatment with PLX5622, which also targets CSF1R, prevented the association of microglia with plaques and improved cognition in the 3xTg-AD mouse model of AD189.”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [189]
Pharmacological blockade of CSF1 receptors impairs microglial survival and can completely remove microglia from the mouse brain.
“Pharmacological blockade of CSF1 receptors has been shown to impair microglial survival and can completely remove microglia from the mouse brain (53–55).”
From <i>Trem2</i> promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [54]
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“We first wanted to establish an appropriate treatment paradigm for microglial elimination and repopulation with the selective CSF1R antagonist PLX5622 (Acharya et al., 2016; Dagher et al., 2015; Klein et al., 2015; Schreiner et al., 2015; Valdearcos et al., 2014), a more brainpenetrant and specific sister molecule of…”
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“Pharmacological blockade of CSF1 receptors has been shown to impair microglial survival and can completely remove microglia from the mouse brain (Dagher et al. 2015; Elmore et al. 2014; Olmos-Alonso et al. 2016).”
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- Authors
- Dagher, N. N., Najafi, A. R., Kayala, K. M. N., Elmore, M. R. P., White, T. E., Medeiros, R., West, B. L., & Green, K. N.
- Affiliations
- University of California, Irvine (US)
- Plexxikon (United States) (US)
- Corresponding author
- Green, Kim N.
- Venue
- Journal of Neuroinflammation
- Published
- 2015-08-01
- Volume
- 12
- Issue
- 1
- Pages
- 139-139
- ISSN
- 1742-2094 (ISSN-L)
- PMC
- PMC4522109
- OpenAlex
- W2127381922
- Cited by
- 505
- References
- 36
- Citations by year
- 2026: 25 · 2025: 39 · 2024: 54 · 2023: 46 · 2022: 66 · 2021: 73 · 2020: 62 · 2019: 49 · 2018: 46 · 2017: 28 · 2016: 15 · 2015: 1
- FWCI
- 16.00
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Journal of Neuroinflammation (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (1RO1NS083801, P50 AG016573, AG00538)
- Whitehall Foundation (ᅟ)
- American Federation for Aging Research (ᅟ)
- Alzheimer's Association (ᅟ)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- CSF1R inhibition, PLX5622, microglia, Alzheimer's disease, 3xTg-AD mice, amyloid plaques, cognitive impairment, microglial depletion, dose-dependent effects, neuroinflammation, learning and memory
- MeSH terms
- Alzheimer Disease, Animals, Anxiety, Brain, Cell Count, Cell Line, Chemotaxis, Cognition Disorders, Dose-Response Relationship, Drug, Humans, Learning, Memory, Mice, Transgenic, Motor Activity, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor, Microglia, Mice, Plaque, Amyloid
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