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Cited by 80Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsNeurological Disease Mechanisms and Treatments

Heterozygous CX3CR1 Deficiency in Microglia Restores Neuronal β-Amyloid Clearance Pathways and Slows Progression of Alzheimer's Like-Disease in PS1-APP Mice

Open access
Hickman, Suzanne E., Allison, Elizabeth K., Coleman, Uwanda, Kingery-Gallagher, Nathan D., El Khoury, Joseph·2019·Frontiers in Immunology
DOI 10.3389/fimmu.2019.02780PMC PMC6900980
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Abstract

CX3CR1 is a chemokine receptor expressed on microglia that binds Fractalkine (CX3CL1) and regulates microglial recruitment to sites of neuroinflammation. Full deletion of CX3CR1 in mouse models of Alzheimer’s disease have opposing effects on amyloid-β and tau pathologies raising concerns about the benefits of targeting CX3CR1 for treatment of this disease. Since most therapies achieve only partial blockade of their targets, we investigated the effects of partial CX3CR1 deficiency on the development and progression of amyloid-β deposition in the PS1-APP Alzheimer’s mouse model. We generated PS1-APP mice heterozygous for CX3CR1 (PS1-APP-CX3CR1+/-) and analyzed these mice for Alzheimer’s-like pathology. We found that partial CX3CR1 deficiency was associated with a significant reduction in Aβ levels and in senile-like plaque load in the brain as compared with age-matched PS1-APP mice. Reduced Aβ level in the brain was associated with improved cognitive function. Levels of the neuronal-expressed Aβ-degrading enzymes insulysin and matrix metalloproteinase 9, which are reduced in the brains of regular PS1-APP mice, were significantly higher in PS1-APP-CX3CR1+/- mice. Our data indicate that lowering CX3CR1 levels or partially inhibiting its activity in the brain may be a therapeutic strategy to increase neuronal Aβ clearance, reduce Aβ levels and delay progression of Alzheimer’s-Like disease. Our findings also suggest a novel pathway where microglial CX3CR1 can regulates gene expression in neurons.

AI snapshot

Written from the paper’s full text.

TL;DR

Partial (heterozygous) CX3CR1 deficiency in PS1-APP mice reduced brain Aβ levels and plaque load, preserved neuronal Aβ-degrading enzyme expression, and improved spatial learning. The findings suggest that partial CX3CR1 blockade, rather than complete deletion, may slow Alzheimer’s-like disease progression in this mouse model.

Key findings

  • At 10 months, PS1-APP-CX3CR1+/− mice had fewer Aβ deposits than PS1-APP mice: 818 ± 81 vs. 1,409 ± 189 deposits, a reduction to 58% (p = 0.006); Aβ-deposit area fraction (AβAF) fell to 60% of PS1-APP values (0.015 ± 0.0017 vs. 0.025 ± 0.0038, p = 0.035).
  • Brain Aβ was lower in PS1-APP-CX3CR1+/− mice: Aβ(1-42) decreased 2.6-fold (7.56 ± 0.41 vs. 19.8 ± 2.6 ng/mg brain, p = 0.0004), and Aβ(1-40) decreased 3.5-fold (0.10 ± 0.011 vs. 0.35 ± 0.039 ng/mg brain, p = 0.0005).
  • Reduced Aβ load occurred early and late: at 5 months, AβAF was reduced 5.5-fold (0.0011 ± 0.0003 vs. 0.0061 ± 0.0009, p = 0.001); at 24 months, AβAF was reduced 38% (0.027 ± 0.003 vs. 0.044 ± 0.0034, p = 0.02).
  • Whole-brain IDE RNA was higher in PS1-APP-CX3CR1+/− mice than PS1-APP mice (43% ± 5.1 vs. 19.0% ± 2.0 of control, p = 0.003), and MMP9 RNA was 69% higher (56.9% ± 3.9 vs. 33.6% ± 3.5 of control, p = 0.004); however, these enzymes were not restored in isolated microglia. On Barnes maze Day 4, PS1-APP-CX3CR1+/− mice had shorter escape latency than PS1-APP mice (16.27 ± 2.06 s vs. 34.9 ± 7.13 s, p < 0.05).

Methods

  • Generated PS1-APP mice heterozygous or null for CX3CR1 and analyzed male mice from 5 to 24 months of age; 10-month cohorts included n = 6 PS1-APP, n = 7 PS1-APP-CX3CR1+/−, and n = 3 PS1-APP-CX3CR1−/−.
  • Measured Aβ plaque number and area fraction by immunofluorescence, Aβ(1-42) and Aβ(1-40) by ELISA, and IDE, neprilysin, and MMP9 RNA by qPCR in whole brain and isolated CD11b+ microglia.
  • Assessed spatial learning and memory with the Barnes maze at 280–300 days; statistics used Student’s t-test or one-way ANOVA with Tukey analysis, p < 0.05.

Limitations

  • The paper states that experiments used only male mice because of limited availability of different genotypes, so it is unknown whether female mice show similar differences.
  • The paper states that effects on tau pathology remain untested, though the authors are exploring combined Aβ/tau models; it also notes that IDE detection in microglia and astrocytes may be limited by staining sensitivity.
  • Evident from the text: sample sizes are small, especially for PS1-APP-CX3CR1−/− mice at 10 months (n = 3), and some results are reported as “data not shown” (neprilysin, T maze, open field), limiting independent assessment.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3389/fimmu.2019.02780

Cites

30 of 30 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

22 of 32 cited sources checked · 15 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Progression of Alzheimer's disease is associated with reduced Aβ-clearing pathways resulting in Aβ accumulation.

    “Progression of Alzheimer's disease is associated with reduced Aβ-clearing pathways resulting in Aβ accumulation (4–6).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [4] El Khoury, 2009

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [5] Hickman, 2008, Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer's disease mice, J Neurosci source

      The Discussion reports that, as AD-like pathology progresses in PS1-APP mice, microglia show reduced Aβ uptake and degradation alongside increased Aβ accumulation. The citing sentence states this as a general feature of Alzheimer's disease progression, whereas the paper's direct evidence comes from a mouse model. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [6] Hickman, 2013, The neuroimmune system in Alzheimer's disease: the glass is half full, J Alzheimers Dis source

      In the section on persistent Aβ deposition, the paper reports reduced Aβ-binding receptors and degrading enzymes as AD-like pathology progresses in PS1-APP mice. It proposes that diminished clearance leads to greater Aβ accumulation, but presents that link as a possibility rather than an established result for Alzheimer's disease generally. The supplied passages have no page numbers. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
  • Premisecitation

    Expression of IDE in microglia from PS1-APP mice decreases with age and progression of AD-like pathology.

    “We have previously shown that expression of IDE in microglia from PS1-APP mice decreases with age and progression of AD-like pathology (5).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [5] Hickman, 2008, Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer's disease mice, J Neurosci source
  • Findingown data

    Partial CX3CR1 deficiency is associated with a significant reduction in Aβ levels in the brain compared with age-matched PS1-APP mice.

    “We found that partial CX3CR1 deficiency was associated with a significant reduction in Aβ levels and in senile-like plaque load in the brain as compared with age-matched PS1-APP mice.”
    • Also stated in: § CX3CR1 Deficiency Is Associated With Reduced Plaque Load and Reduced Aβ Levels in PS1-APP Mice · hedged
      “These data indicate that partial CX3CR1 deficiency in heterozygous PS1-APP-CX3CR+/− is associated with a significant reduction in Aβ deposits and load and in the levels of Aβ (1-42) and (1-40) compared to PS1-APP mice and that complete deletion of CX3CR1 is not necessary to confer beneficial effects on AD-like pathology in these mice.”
    Quote in the paperSubstantial claim
  • Findingown data

    Partial CX3CR1 deficiency is associated with a significant reduction in senile-like plaque load in the brain compared with age-matched PS1-APP mice.

    “We found that partial CX3CR1 deficiency was associated with a significant reduction in Aβ levels and in senile-like plaque load in the brain as compared with age-matched PS1-APP mice.”
    • Also stated in: § CX3CR1 Deficiency Is Associated With Reduced Plaque Load and Reduced Aβ Levels in PS1-APP Mice · hedged
      “These data indicate that partial CX3CR1 deficiency in heterozygous PS1-APP-CX3CR+/− is associated with a significant reduction in Aβ deposits and load and in the levels of Aβ (1-42) and (1-40) compared to PS1-APP mice and that complete deletion of CX3CR1 is not necessary to confer beneficial effects on AD-like pathology in these mice.”
    Quote in the paperSubstantial claim
  • Findingown data

    Levels of the neuronal-expressed Aβ-degrading enzyme matrix metalloproteinase 9 (MMP9) are significantly higher in PS1-APP-CX3CR1+/− mice than in PS1-APP mice.

    “Levels of the neuronal-expressed Aβ-degrading enzymes insulysin and matrix metalloproteinase 9, which are reduced in the brains of regular PS1-APP mice, were significantly higher in PS1-APP-CX3CR1+/− mice.”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 12
  • May combine two claims. 18

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    CX3CR1 and its ligand fractalkine have been implicated in recruitment of mononuclear phagocytes to sites of inflammation and injury and play roles in the pathogenesis of several inflammatory conditions including atherosclerosis, neuropathic pain, and asthma.

    “CX3CR1 and its chemokine ligand fractalkine (CX3CL1) have been implicated in the recruitment of mononuclear phagocytes to sites of inflammation and injury (7, 10, 11) and play roles in the pathogenesis of several inflammatory conditions, including atherosclerosis (12, 13), neuropathic pain (14), and asthma (15).”
    Quote in the paperNot a substantial claim3 of 7 sources checked
    • cites [7] Bazan, 1997, A new class of membrane-bound chemokine with a CX3C motif, Nature. source
    • cites [10] Hughes, 2002, Expression of fractalkine (CX3CL1) and its receptor, CX3CR1, during acute and chronic inflammation in the rodent CNS, Glia. source
    • cites [11] D'Haese, 2010, Fractalkine/CX3CR1: why a single chemokine-receptor duo bears a major and unique therapeutic potential, Expert Opin Ther Targets. source
    • cites [12] Combadiere, 2003, Decreased atherosclerotic lesion formation in CX3CR1/apolipoprotein E double knockout mice, Circulation. source
    • cites [13] Lesnik, 2003, Decreased atherosclerosis in CX3CR1−/− mice reveals a role for fractalkine in atherogenesis, J Clin Invest. source
    • cites [14] Zhuang, 2007, Role of the CX3CR1/p38 MAPK pathway in spinal microglia for the development of neuropathic pain following nerve injury-induced cleavage of fractalkine, Brain Behav Immun. source
    • cites [15] Rimaniol, 2003, The CX3C chemokine fractalkine in allergic asthma and rhinitis, J Allergy Clin Immunol. source

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    CX3CR1 is a chemokine receptor expressed on microglia and a subset of monocytes.

    “CX3CR1 is a chemokine receptor expressed on microglia and a subset of monocytes (8, 9).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [8] Hickman, 2010, Mechanisms of mononuclear phagocyte recruitment in Alzheimer's disease, CNS Neurol Disord Drug Targets. source

      The “Chemokines and Accumulation of Mononuclear Phagocytes in AD” section identifies CX3CR1 as the fractalkine receptor, and “Additional Chemokines that may also Control Microglia Accumulation in AD” says it is highly expressed on microglia. The “Recruitment of Monocytes into the AD Brain” section links CX3CR1 to monocyte trafficking, but our copy does not specify that its expression is limited to a subset of monocytes. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [9] Hickman, 2013, The microglial sensome revealed by direct RNA sequencing, Nat Neurosci source

      The Results section, “Microglia vs. Macrophages” (page not specified), identifies Cx3cr1 among chemokine-receptor genes expressed at higher levels in microglia than in peritoneal macrophages. The paper does not establish expression in a subset of monocytes; its comparison is with macrophages, not monocytes. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In Alzheimer's disease, complete deletion of CX3CR1 in models of amyloid deposition reduced Aβ deposits and enhanced microglial Aβ phagocytic ability.

    “In Alzheimer's disease complete deletion of CX3CR1 in models of amyloid deposition reduced Aβ deposits and enhanced microglial Aβ phagocytic ability (16, 17).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [16] Lee, 2010, CX3CR1 deficiency alters microglial activation and reduces beta-amyloid deposition in two Alzheimer's disease mouse models, Am J Pathol. source
    • cites [17] Liu, 2010, CX3CR1 in microglia regulates brain amyloid deposition through selective protofibrillar amyloid-beta phagocytosis, J Neurosci source

  • Classified as probably not a substantial claim.

    Interpretationcitation

    Targeting CX3CR1 activity may be a therapeutic strategy to lower Aβ levels.

    “These studies provided important insight on the role of CX3CR1 in AD and suggested that targeting CX3CR1 activity may be a therapeutic strategy to lower Aβ levels.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [16] Lee, 2010, CX3CR1 deficiency alters microglial activation and reduces beta-amyloid deposition in two Alzheimer's disease mouse models, Am J Pathol. source
    • cites [17] Liu, 2010, CX3CR1 in microglia regulates brain amyloid deposition through selective protofibrillar amyloid-beta phagocytosis, J Neurosci source
    • Rests on an assumption: Pharmacologic targeting of CX3CR1 is unlikely to achieve the effects of complete deletion of this receptor as in CX3CR1−/− mice.

  • May combine two claims.

    Premisecitation

    MMP9 is an important Aβ-degrading enzyme expressed on microglia and neurons.

    “MMP9 is an important Aβ-degrading enzyme expressed on microglia (25) and neurons (26).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [25] Paglinawan, 2003, TGFbeta directs gene expression of activated microglia to an anti-inflammatory phenotype strongly focusing on chemokine genes and cell migratory genes, Glia source
    • cites [26] Maolood, 2008, Matrix metalloproteinases MMP2 and MMP9 are upregulated by noradrenaline in the mouse neuroendocrine hypothalamus, Eur J Neurosci source

  • May combine two claims.

    Premisecitation

    Progression of Alzheimer's disease in humans and mouse models of the disease is associated with reduced expression of these Aβ-clearing enzymes resulting in decreased Aβ clearance and increased Aβ accumulation.

    “Progression of Alzheimer's disease in humans and mouse models of the disease is associated with reduced expression of these Aβ-clearing enzymes resulting in decreased Aβ clearance and increased Aβ accumulation (5, 24).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [5] Hickman, 2008, Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer's disease mice, J Neurosci source

      The Results section reports reduced expression of Aβ-degrading enzymes in microglia from older PS1-APP mice, and the Discussion links reduced enzyme expression to reduced Aβ degradation and increased accumulation. The paper does not establish the same enzyme-expression change in humans, so the claim’s extension to human Alzheimer’s disease is unsupported by this source. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [24] Miller, 2003, Amyloid-beta peptide levels in brain are inversely correlated with insulysin activity levels in vivo, Proc Natl Acad Sci USA source

      The Results and Discussion (page numbers unavailable) show that genetically reduced insulysin expression and activity in mice accompanied increased brain Aβ, and the authors infer that insulysin helps degrade Aβ in vivo. The paper does not establish that progression of Alzheimer’s disease in humans or disease-model mice is accompanied by declining expression of multiple Aβ-clearing enzymes; it suggests a possible link to disease risk instead. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Microglia do not exist statically in the brain but actively patrol their immediate environment by constant extension and retraction of dendritic-like arms.

    “Microglia do not exist statically in the brain but actively patrol their immediate environment by constant extension and retraction of dendritic-like arms (31).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [31] Hickman, 2018, Microglia in neurodegeneration, Nat Neurosci source

  • May combine two claims.

    Premisecitation

    Complete deletion of CX3CR1 is associated with worsening memory deficits and tau pathology.

    “However, such complete deletion has also been associated with worsening memory deficits and tau pathology (28–31).”
    Quote in the paperSubstantial claim4 of 4 sources checked
    • cites [28] Bhaskar, 2010, Regulation of tau pathology by the microglial fractalkine receptor, Neuron. source
    • cites [29] Cho, 2011, CX3CR1 protein signaling modulates microglial activation and protects against plaque-independent cognitive deficits in a mouse model of Alzheimer disease, J Biol Chem source
    • cites [30] Guedes, 2018, Roles of microglial and monocyte chemokines and their receptors in regulating Alzheimer's disease-associated amyloid-beta and tau pathologies, Front Neurol source
    • cites [31] Hickman, 2018, Microglia in neurodegeneration, Nat Neurosci source

      The Cx3cr1–fractalkine > AD section says Cx3cr1 deficiency worsens tau pathology in mouse models. It does not report worsening memory deficits from complete CX3CR1 deletion, so that part of the claim is unsupported by our copy. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Complete deletion of CX3CR1 in models of amyloid deposition reduces Aβ deposits and enhances microglial Aβ phagocytosis.

    “Complete deletion of CX3CR1 in models of amyloid deposition have been shown to reduce Aβ deposits and enhanced microglial Aβ phagocytosis (16, 17).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [16] Lee, 2010, CX3CR1 deficiency alters microglial activation and reduces beta-amyloid deposition in two Alzheimer's disease mouse models, Am J Pathol. source
    • cites [17] Liu, 2010, CX3CR1 in microglia regulates brain amyloid deposition through selective protofibrillar amyloid-beta phagocytosis, J Neurosci source

  • May combine two claims.

    Findingnone given

    Partial CX3CR1 deficiency is associated with lower Aβ levels and decreased plaque load in PS1-APP mice.

    “Because partial CX3CR1 deficiency is associated with lower Aβ levels and decreased plaque load in PS1-APP mice, we hypothesized that under pathological conditions such as AD, CX3CR1 may regulate expression of Aβ degrading enzymes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Co-staining showed very little co-staining of IDE in GFAP-containing cells and intense staining for IDE in cells lacking GFAP.

    “Co-staining for IDE (red) and GFAP (green, Figure 4B) showed very little co-staining of IDE in GFAP containing cells and intense staining for IDE in cells lacking GFAP.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Partial microglial CX3CR1 deficiency reverses or slows the reduction in insulysin and MMP9 Aβ-degrading enzymes observed in PS1-APP mice as they age and their AD-like pathology progresses.

    “Indeed, by examining the gene expression profile of whole brains and of purified microglia, we found that partial microglial CX3CR1 deficiency reverses or slows the reduction in insulysin and MMP9 Aβ-degrading enzymes observed in PS1-APP mice as they age, and their AD-like pathology progresses.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    WT and PS1-APP-CX3CR1+/− mice navigated to the escape box quickly, while PS1-APP mice tended to meander and hesitated longer before identifying the correct hole.

    “WT and PS1-APP-CX3CR1+/− mice navigated to the escape box quickly, while the PS1-APP mice tended to meander and hesitated longer before identifying the correct hole with the escape box.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    In the T maze, a similar trend was observed but differences did not reach statistical significance.

    “A similar trend was observed when the mice were tested in the T maze, another test for spatial learning, but the differences did not reach statistical significance (data not shown).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Chemokines are chemotactic cytokines that control recruitment of mononuclear phagocytes to sites of inflammation.

    “Chemokines are chemotactic cytokines that control recruitment of mononuclear phagocytes to sites of inflammation (7).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Bazan, 1997, A new class of membrane-bound chemokine with a CX3C motif, Nature. source

  • May combine two claims.

    Interpretationown data

    Lowering CX3CR1 levels or partially inhibiting its activity in the brain may be a therapeutic strategy to increase neuronal Aβ clearance, reduce Aβ levels and delay progression of Alzheimer's-Like disease.

    “Our data indicate that lowering CX3CR1 levels or partially inhibiting its activity in the brain may be a therapeutic strategy to increase neuronal Aβ clearance, reduce Aβ levels and delay progression of Alzheimer's-Like disease.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Partial inhibition of CX3CR1 activity can be achieved pharmacologically, similar to what is observed in mice heterozygous for this receptor.
    • Rests on an assumption: Pharmacologic targeting of CX3CR1 is unlikely to achieve the effects of complete deletion of this receptor as in CX3CR1−/− mice.

  • Classified as probably not a substantial claim.

    Premisecitation

    Aβ levels in the brain are regulated in part by several Aβ-degrading enzymes, including insulin degrading enzyme (IDE-insulysin), neprilysin and matrix metalloprotease 9 (MMP9).

    “Aβ levels in the brain are regulated in part by several Aβ-degrading enzymes, including insulin degrading enzyme (IDE-insulysin), neprilysin and matrix metalloprotease 9 (MMP9) (4).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4] El Khoury, 2009

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The number of CD11b positive cells associated with plaques ≥75 μm in largest diameter was quantified by two independent blinded laboratory members.

    “the number of CD11b positive cells associated with plaques ≥75 μm in their largest diameter was quantified by two independent blinded laboratory members.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Partial CX3CR1 deficiency slows the accumulation of Aβ in PS1-APP mice starting early in the disease process and continues to do so at late disease stages.

    “These data indicate that partial CX3CR1 deficiency slows the accumulation of Aβ in PS1-APP mice starting early in the disease process and continues to do so at late disease stages.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    The Barnes maze protocol used allowed detection of spatial learning deficits in PS1-APP mice trained first with the cued version followed by the non-cued version.

    “We used a protocol that allowed detection of spatial learning deficits in PS1-APP mice that had been trained first with the cued version followed by the non-cued version (23).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Reiserer, 2007, Impaired spatial learning in the APPSwe + PSEN1DeltaE9 bigenic mouse model of Alzheimer's disease, Genes Brain Behav. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductreasoning

    Only male mice were used at ages ranging from 5 to 24 months.

    “Because of the limited number of mice that can be generated, only male mice were used at ages ranging from 5 to 24 months and euthanized according to approved institutional procedures.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    A minimum of 80 plaques were counted per genotype.

    “A minimum of 80 plaques were counted per genotype.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Partial CX3CR1 deletion restores the beneficial effects of lowering Aβ levels and improves behavioral/cognitive testing.

    “Our findings show that partial CX3CR1 deletion restores the beneficial effects of lowering Aβ levels and show improvement in behavioral/cognitive testing.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Partial CX3CR1 deficiency slows progression of AD-like pathology in a transgenic mouse model of the disease and reverses cognitive deficit, by restoring neuronal Aβ-degrading pathways possibly by disrupting CX3CR1-fractalkine interactions.

    “Collectively, our data indicate that partial CX3CR1 deficiency slows progression of AD-like pathology in a transgenic mouse model of the disease and reverses cognitive deficit, by restoring neuronal Aβ-degrading pathways possibly by disrupting CX3CR1-fractalkine interactions.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    These experiments were performed in male mice due to limited availability of mice of different genotypes.

    “It is important to note when interpreting our findings is that due to limited availability of mice of different genotypes, these experiments were performed in male mice.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    MMP9 is highly expressed in microglia but is also expressed in other cells of the brain.

    “In contrast, expression of MMP9 in WT microglia was 6-fold higher than in whole brain (0.0062 ± 0.0018 vs. 0.00097 ± 0.00015, respectively) indicating that MMP9 is highly expressed in microglia but is also expressed in other cells of the brain.”
    Quote in the paperSubstantial claim
26 of 26

  • The paper relies on this without support.

    Partial inhibition of CX3CR1 activity can be achieved pharmacologically, similar to what is observed in mice heterozygous for this receptor.

    “However, it is possible to achieve partial inhibition of CX3CR1 activity pharmacologically, similar to what is observed in mice heterozygous for this receptor (CX3CR1+/−).”

  • The paper relies on this without support.

    Neuronal fractalkine is the only known ligand for CX3CR1.

    “Since neuronal fractalkine is the only known ligand for CX3CR1, our results also suggest a novel pathway through which microglia can regulate neuronal gene expression possibly via CX3CR1-fractalkine interactions.”

  • The paper relies on this without support.

    Pharmacologic targeting of CX3CR1 is unlikely to achieve the effects of complete deletion of this receptor as in CX3CR1−/− mice.

    “It is unlikely that pharmacologic targeting of CX3CR1 will achieve the effects of complete deletion of this receptor as in CX3CR1−/− mice.”

  • The paper relies on this without support.

    The number of microglia harvested per hemisphere reflects the total number of microglia in the brain.

    “we quantified the total number of microglia harvested per hemisphere of PS1-APP-CX3CR1+/− and PS1-APP mice and found no statistically significant differences between the two genotypes (Figure 2C).”

  • The paper relies on this without support.

    The number of CD11b+ cells associated per plaque ≥75 μm reflects microglial accumulation at sites of Aβ accumulation.

    “We also compared the numbers of CD11b+ cells associated per plaque and found that when comparing same size plaques (≥75 μm) there were no statistically significant differences between the two genotypes (Figures 2D,E).”

  • The paper relies on this without support.

    The only known ligand for microglial CX3CR1 is neuronal fractalkine.

    “Because the only known ligand for microglial CX3CR1 is neuronal fractalkine, these findings suggest that interactions of microglial CX3CR1 with neuronal fractalkine regulate gene expression in neurons.”
6 of 6

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Targeting microglia with the Cx3cr1ERT2cre strategy leads to improved clearance of Aβ and ameliorated disease progression in the APP/PS1 mouse model of AD.

    “in a recent study it was shown that targeting microglia with this strategy actually leads to improved clearance of Aβ and ameliorated disease progression in the APP/PS1 mouse model of AD (Hickman et al., 2019)”

    From SYK coordinates neuroprotective microglial responses in neurodegenerative disease (2022) · cites this paper as Hickman et al., 2019

    The Introduction and Discussion report that partial CX3CR1 deficiency in PS1-APP mice reduced Aβ levels and plaques, improved cognitive testing, and was associated with restored neuronal Aβ-degrading enzymes. But Materials and Methods (Mice; page unavailable) describes a CX3CR1-GFP replacement allele, not the Cx3cr1ERT2cre strategy attributed to the study. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • NOX1 expression may be an artefact of the Cx3cr1-EGFP reporter line.

    “NOX1 expression may be an artefact of the Cx3cr1-EGFP reporter line, since Cx3cr1 is a signature microglial gene and haploinsufficiency has wide-reaching effects on gene expression of microglia, specifically encouraging a prematurely aged transcriptome [78,79,80].”

    From ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease (2020) · cites this paper as [79]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Conflicting duration of cued Barnes maze training

    Minor

    The Figure 7 caption reports five days of cued-target training, but the methods specify four consecutive days for the cued-variable session, with a probe trial on the fifth day.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. El Khoury, 2009, Mechanism of Amyloid Beta clearance in Alzheimer's disease in Research Progress in Alzheimer's Disease and Dementia (Vol 4).

Cited by

Sorted by citations

Related

Authors
Hickman, S. E., Allison, E. K., Coleman, U., Kingery-Gallagher, N. D., & El Khoury, J.
Affiliations
Harvard University (US)
ORCID
Hickman, Suzanne E.
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2019-12-02
Volume
10
Pages
2780-2780
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2019.02780
PMC
PMC6900980
OpenAlex
W2988505515
Semantic Scholar
75ce8a6806ceed2182507d67c5ac0ab417772b96
Cited by
80
References
30
Citations by year
2026: 5 · 2025: 11 · 2024: 13 · 2023: 17 · 2022: 8 · 2021: 13 · 2020: 13
FWCI
4.84
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (submittedVersion, cc-by)
  • PubMed Central (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • National Institute on Aging
  • Dana Foundation
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
CX3CR1, heterozygous deficiency, microglia, Alzheimer's disease, amyloid-beta clearance, amyloid plaques, MMP-9, cognitive function, neuroinflammation, chemokine receptors, therapeutic target
MeSH terms
CX3C Chemokine Receptor 1, Alzheimer Disease, Animals, Behavior, Animal, Disease Models, Animal, Heterozygote, Mice, Transgenic, Neurons, Signal Transduction, Amyloid beta-Peptides, Microglia, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-20.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-20.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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