CX3CR1 in Microglia Regulates Brain Amyloid Deposition through Selective Protofibrillar Amyloid-β Phagocytosis
Open accessAbstract
In Alzheimer's disease (AD), amyloid-β (Aβ) deposits are frequently surrounded by activated microglia but the precise role of these cells in disease progression remains unclear. The chemokine receptor CX3CR1 is selectively expressed in microglia and is thought to modulate their activity. To study the specific effects of microglia activation on amyloid pathology in vivo, we crossbred mice lacking CX3CR1 with the Alzheimer's mouse model CRND8. Surprisingly, we found that CX3CR1-deficient mice had lower brain levels of Aβ40 and Aβ42 and reduced amyloid deposits. Quantification of Aβ within microglia and time-lapse two-photon microscopy in live mice revealed that these cells were highly effective at the uptake of protofibrillar amyloid but were incapable of phagocytosis of fibrillar congophilic Aβ. CX3CR1 deletion was associated with increased phagocytic ability, which led to greater amyloid content within microglial phagolysosomes. Furthermore, CX3CR1-deficient mice had an increased number of microglia around individual plaques because of higher proliferative rates, which likely contributed to an overall greater phagocytic capacity. CX3CR1 deletion did not affect the degree of neuronal or synaptic damage around plaques despite increased microglia density. Our results demonstrate that microglia can regulate brain Aβ levels and plaque deposition via selective protofibrillar Aβ phagocytosis. Modulation of microglia activity and proliferation by CX3CR1 signaling may represent a therapeutic strategy for AD.
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Claims the paper makes
12 of 24 cited sources checked · 5 supported · 0 flagged · accuracy not yet measured
- Interpretationcitation
Microglia may only be able to remove fibrillar amyloid from plaques during heightened levels of activation such as in injury models or after Aβ immunization.
“Thus microglia may only be able to remove fibrillar amyloid from plaques during heightened levels of activation such as in injury models (DiCarlo et al., 2001) or after Aβ immunization (Bacskai et al., 2002).”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites DiCarlo et al., 2001
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites Bacskai et al., 2002 source
The introduction links microglial activation after topical antibody treatment to a possible Fc-mediated clearance mechanism, and the Results report clearance of some dense-core plaques after antibody treatment. But the paper does not establish that microglia themselves cleared those plaques or that heightened activation is required; it also finds evidence for non-Fc-mediated clearance. Its experiments used topical antibodies, not Aβ immunization. (LLM, conf=0.85)
Experimental — accuracy not yet measured
- Interpretationcitation
CX3CR1 modulation of phagocytosis may involve the indirect effect of proinflammatory cytokines which can attenuate phagocytosis.
“Thus, CX3CR1 modulation of phagocytosis may involve the indirect effect of some proinflammatory cytokines which can attenuate phagocytosis (Koenigsknecht-Talboo and Landreth, 2005).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Koenigsknecht-Talboo and Landreth, 2005 source
- Interpretationcitation
Fractalkine through its receptor CX3CR1 acts as a repressor of microglia activation.
“Our findings support the concept that fractalkine through its receptor CX3CR1 (Harrison et al., 1998) acts as a repressor of microglia activation (Cardona et al., 2006).”
Quote in the paperSubstantial claim1 of 2 sources checked- Rests on an assumption: CX3CR1 is specifically expressed in microglia in the brain.
- Findingown data
There was complete stability of the Aβ42 (HiLyte)-555 label in plaques at least over a 90 day interval.
“However, we found complete stability of the label at least over this 90 day interval (Figure 3B, C).”
Quote in the paperSubstantial claim- Rests on an assumption: Fluorescently labeled Aβ42 (HiLyte-555) behaves like endogenous Aβ42 in binding, stability, and phagocytosis.
- Findingown data
Once bound to plaques, Aβ42 was highly stable over many weeks.
“Once bound to plaques, we found by time-lapse imaging that Aβ42 was highly stable over many weeks like we observed with methoxy-XO4.”
Quote in the paperSubstantial claim- Rests on an assumption: Fluorescently labeled Aβ42 (HiLyte-555) behaves like endogenous Aβ42 in binding, stability, and phagocytosis.
- Findingown data
Microglia of each genotype represent approximately 50% of the total microglia population in mixed cell cultures.
“Microglia of each genotype represent ~50% of the total microglia population in these mixed cell cultures.”
Quote in the paperNot a substantial claim - Findingown data
Time-lapse TPM images over intervals up to 1 month showed virtually no change in the size or shape of the original fluorescent plaque label.
“However, time-lapse TPM images over intervals of up to 1 month showed virtually no change in the size or shape of the original fluorescent plaque label (Figure 2A, B).”
Quote in the paperSubstantial claim- Rests on an assumption: In vivo two-photon imaging through a thinned skull does not alter microglial phagocytic behavior or plaque stability.
- Findingown data
At 2 months of age, both CRND8/CX3CR1−/− mice and CRND8/CX3CR1+/+ littermates had low levels of total brain Aβ40 and Aβ42 peptides.
“At 2 months of age, both CRND8/CX3CR1−/− mice and their wild-type littermates (CRND8/CX3CR1+/+) demonstrated low levels of total brain Aβ40 and Aβ42 peptides (Figures 1A, B).”
Quote in the paperNot a substantial claim- Rests on an assumption: The CRND8 mouse model of amyloid deposition is relevant to human Alzheimer's disease.
- Findingown data
CRND8/CX3CR1−/− mice had a significantly reduced number of amyloid plaques at both 3 and 5 months of age compared with CRND8/CX3CR1+/+ mice.
“reduced amyloid deposits”
- Also stated in: § CX3CR1 deficiency in microglia leads to reduced brain β-amyloid load and deposition · plain
“We found that CRND8/CX3CR1−/− mice had a significantly reduced number of amyloid plaques at both 3 and 5 months of age (Figure 1C, D).”
Quote in the paperSubstantial claim- Rests on an assumption: The CRND8 mouse model of amyloid deposition is relevant to human Alzheimer's disease.
- Also stated in: § CX3CR1 deficiency in microglia leads to reduced brain β-amyloid load and deposition · plain
- Findingown data
The increased number of microglia around plaques in CX3CR1 deficient mice was due to higher proliferative rates.
“Furthermore, CX3CR1 deficient mice had an increased number of microglia around individual plaques due to higher proliferative rates, which likely contributed to an overall greater phagocytic capacity.”
Quote in the paperNot a substantial claim - Findingown data
CX3CR1 deficient mice had an increased number of microglia around individual plaques.
“Furthermore, CX3CR1 deficient mice had an increased number of microglia around individual plaques due to higher proliferative rates, which likely contributed to an overall greater phagocytic capacity.”
Quote in the paperSubstantial claim - Findingown data
Quantification of TS fluorescence within IBA1-immunolabeled cells revealed absence of any intracellular TS labeling regardless of CX3CR1 genotype.
“Quantification of TS fluorescence within IBA1-immunolabeled cells revealed absence of any intracellular TS labeling (Figure 2C, D) regardless of the CX3CR1 genotype (Figure 2D).”
Quote in the paperSubstantial claim- Rests on an assumption: The absence of intracellular Thioflavin-S labeling indicates lack of phagocytosis of fibrillar amyloid rather than rapid degradation or masking of the label.
- Findingcitation
Non-plaque areas immediately adjacent to plaques demonstrated very low fluorescence levels after Aβ42 infusion.
“However, non-plaque areas immediately adjacent demonstrated very low fluorescence levels (Figure 3A) suggesting that unbound Aβ42 was rapidly cleared possibly through the blood brain barrier (DeMattos et al., 2002).”
Quote in the paperNot a substantial claim- Rests on an assumption: Fluorescently labeled Aβ42 (HiLyte-555) behaves like endogenous Aβ42 in binding, stability, and phagocytosis.
- Findingown data
Microglia are highly effective at the uptake of protofibrillar amyloid.
“these cells were highly effective at the uptake of protofibrillar amyloid but were incapable of phagocytosis of fibrillar congophilic Aβ.”
Quote in the paperSubstantial claim - Findingown data
Microglia are unable to phagocytose fibrillar congophilic amyloid in vivo.
“were incapable of phagocytosis of fibrillar congophilic Aβ”
- Also stated in: § Microglia are unable to phagocytose fibrillar congophilic amyloid in vivo · plain
“Microglia are unable to phagocytose fibrillar congophilic amyloid in vivo”
- Also stated in: § INTRODUCTION · plain
“microglia were incapable of phagocytosis of congophilic fibrillar amyloid from plaques”
Quote in the paperSubstantial claim- Rests on an assumption: The absence of intracellular Thioflavin-S labeling indicates lack of phagocytosis of fibrillar amyloid rather than rapid degradation or masking of the label.
- Also stated in: § Microglia are unable to phagocytose fibrillar congophilic amyloid in vivo · plain
- Findingreasoning
Little Aβ42(HiLyte)-555 is observed in areas outside plaques in the first 12 hours post infusion.
“However, little Aβ42(HiLyte)-555 was observed in areas outside of plaques in the first 12 hours post infusion, likely due to rapid Aβ efflux through the BBB.”
Quote in the paperNot a substantial claim - Findingown data
Within hours of subarachnoid infusion, Aβ42(HiLyte)-555 strongly binds to preexisting methoxy-XO4-labeled fibrillar amyloid plaques in vivo.
“Within hours of infusion, we observed strong binding of Aβ42(HiLyte)-555 to preexisting methoxy-XO4-labeled fibrillar amyloid plaques as seen by in vivo imaging.”
Quote in the paperNot a substantial claim - Findingown data
During imaging, Aβ42 (HiLyte)-555 infused into the subarachnoid space bound very rapidly (within minutes) to preexisting amyloid plaques.
“During imaging, we observed very rapid binding of Aβ42 (within minutes) to preexisting amyloid plaques (Figure 3A) suggesting a very high affinity of soluble Aβ42 for fibrillar amyloid within plaques.”
Quote in the paperSubstantial claim- Rests on an assumption: Fluorescently labeled Aβ42 (HiLyte-555) behaves like endogenous Aβ42 in binding, stability, and phagocytosis.
- Findingown data
CX3CR1 deletion did not affect the degree of neuronal or synaptic damage around plaques despite increased microglia density.
“CX3CR1 deletion did not affect the degree of neuronal or synaptic damage around plaques despite increased microglia density.”
- Also stated in: § INTRODUCTION · plain
“we found no difference in either neuronal loss or synaptic injury around plaques. This occurred despite significant differences in the density of plaque associated microglia which in their activated status are thought to have neurotoxic potential (Block et al., 2007).”
Quote in the paperSubstantial claim - Also stated in: § INTRODUCTION · plain
- Findingown data
At 5 months, brain Aβ40 and Aβ42 concentrations were significantly lower in CRND8/CX3CR1−/− mice than in CRND8/CX3CR1+/+ littermates.
“CX3CR1 deficient mice had lower brain levels of Aβ40 and Aβ42 and reduced amyloid deposits.”
- Also stated in: § CX3CR1 deficiency in microglia leads to reduced brain β-amyloid load and deposition · plain
“At 5 months, brain Aβ40 and Aβ42 concentrations had risen markedly but were significantly lower in CRND8/CX3CR1−/− mice as compared with CRND8/CX3CR1+/+ littermates (Figures 1A, B).”
Quote in the paperSubstantial claim- Rests on an assumption: The CRND8 mouse model of amyloid deposition is relevant to human Alzheimer's disease.
- Also stated in: § CX3CR1 deficiency in microglia leads to reduced brain β-amyloid load and deposition · plain
- Findingown data
Quantification of Aβ42(HiLyte)-555 fluorescence within individual microglia shows a ~3 fold rise 16 days after subarachnoid infusion.
“Quantification of Aβ42(HiLyte)-555 fluorescence within individual microglia showed a ~3 fold rise 16 days after subarachnoid infusion (Figure 4E).”
Quote in the paperSubstantial claim - Findingown data
There is a greater average number of microglia within a 25 μm radius of the plaque edge in 5 month-old CRND8/CX3CR1−/− mice than in wild-type littermates.
“We found a greater average number of microglia within a 25 μm radius of the plaque edge in 5 month-old CRND8/CX3CR1−/− mice than in wild-type littermates (Figure 7A, B).”
Quote in the paperSubstantial claim - Findingown data
Virtually none of the Aβ42(HiLyte)-555 accumulations co-label with Thioflavin-S.
“Virtually none of these Aβ42(HiLyte)-555 accumulations co-labeled with TS (Figures 4B, D) suggesting that these deposits were composed of material in a protofibrillar Aβ conformation.”
Quote in the paperSubstantial claim - Findingown data
CX3CR1−/− microglia have a greater capacity to uptake both Aβ peptides and microspheres than CX3CR1+/+ microglia in vitro.
“We found that CX3CR1−/− microglia had a greater capacity to uptake both Aβ peptides and microspheres suggesting an overall enhanced phagocytic activity.”
Quote in the paperSubstantial claim - Findingown data
A11 and 4G8 immunofluorescence within LAMP-1 labeled phagolysosomes in microglia is significantly increased in CRND8/CX3CR1−/− mice compared to wild-type littermates.
“We found a significantly increased A11 and 4G8 immunofluorescence in phagolysosomes from CRND8/CX3CR1−/− mice compared to wild-type littermates, suggesting that CX3CR1−/− microglia have an increased capacity to phagocytose endogenously produced amyloid.”
Quote in the paperSubstantial claim - Findingown data
Quantification of NeuN-positive cells and synaptophysin-immunoreactive puncta demonstrates no statistically significant difference between wild type and CX3CR1 deficient mice.
“Quantification of cells with the neuronal nuclear marker NeuN and of synaptophysin immunoreactive puncta demonstrated no statistically significant difference between wild type and CX3CR1 deficient mice (Figure 8).”
Quote in the paperSubstantial claim - Findingown data
The overall proportion of microglia that are BrdU-labeled is significantly greater in CRND8/CX3CR1−/− mice than in CRND8/CX3CR1+/+ littermates.
“Interestingly, we found that the overall proportion of microglia that were BrdU-labeled was significantly greater in CRND8/CX3CR1−/− mice than in CRND8/CX3CR1+/+ littermates (Figure 7C, D), while non-plaque areas showed substantially lower overall proliferation rates and no significant differences between genotypes (Figure 7D).”
Quote in the paperSubstantial claim - Findingown data
Bright clusters of A11 and 4G8-immunoreactive material that do not co-label with Thioflavin-S are found mostly inside LAMP-1-immunoreactive vesicles inside microglia.
“We found bright clusters of A11 and 4G8-immunoreactive material that did not co-label with TS, mostly inside lysosomal-associated membrane protein (LAMP-1)-immunoreactive vesicles inside microglia (Figures 5A-D and supplementary Figure 2).”
Quote in the paperSubstantial claim - Findingcitation
At early time points after infusion, a substantial number of Aβ deposits are observed inside microglia within vesicular compartments consistent with phagolysosomes.
“However, at this early time point a substantial number of deposits were already observed inside microglia within vesicular compartments consistent with phagolysosomes(Frackowiak et al., 1992) (Figure 4A, C and supplementary movie 1).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Frackowiak et al., 1992 source
- Findingown data
At day 16 after infusion, there is a large decrease in the number and intensity of fluorescent Aβ aggregates outside microglia.
“Concurrent with the increase in fluorescence inside microglia, at day 16 there was a large decrease in the number and intensity of fluorescent aggregates outside microglia (Figure 4F) suggesting that these newly formed Aβ deposits were being phagocytosed.”
Quote in the paperSubstantial claim - Findingown data
Beginning at ~24 hours after infusion, scattered fluorescent Aβ deposits become evident.
“Beginning at ~24 hours, however, scattered fluorescent Aβ deposits became evident (Figures 4C) possibly due to aggregation of Aβ42(HiLyte)-555 that failed to be cleared through the BBB or due to binding to pre-existing protofibrillar aggregates.”
Quote in the paperNot a substantial claim - Findingown data
CX3CR1 deficient microglia display enhanced process dynamism over short intervals.
“We found that CX3CR1 deficient microglia display enhanced process dynamism over short intervals (Supplementary Figure 3).”
Quote in the paperNot a substantial claim - Interpretationcitation
This selective phagocytic function may be critical in controlling Aβ deposition as well as levels of potentially neurotoxic Aβ oligomers.
“This function may be critical in controlling Aβ deposition as well as levels of potentially neurotoxic Aβ oligomers (Lambert et al., 1998).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Lambert et al., 1998
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationreasoning
The reduction in Aβ levels and plaque density in CRND8/CX3CR1−/− mice suggests a critical role of microglia and CX3CR1 in controlling Aβ accumulation.
“Given that the expression of CX3CR1 in the brain is microglia specific, the reduction in Aβ levels and plaque density in CRND8/CX3CR1−/− mice suggests a critical role of microglia and CX3CR1 in controlling Aβ accumulation.”
Quote in the paperSubstantial claim- Rests on an assumption: The CRND8 mouse model of amyloid deposition is relevant to human Alzheimer's disease.
- Interpretationreasoning
The low Aβ42(HiLyte)-555 outside plaques in the first 12 hours is likely due to rapid Aβ efflux through the BBB.
“However, little Aβ42(HiLyte)-555 was observed in areas outside of plaques in the first 12 hours post infusion, likely due to rapid Aβ efflux through the BBB.”
Quote in the paperNot a substantial claim - Interpretationown data
The disparity in brain Aβ levels and amyloid plaque number between CX3CR1 genotypes was likely due to reduced Aβ accumulation rather than decreased Aβ production.
“The disparity in brain Aβ levels and amyloid plaque number between CX3CR1 genotypes were likely due to reduced Aβ accumulation rather than decreased Aβ production given that there was no significant difference in amyloid precursor protein (APP) concentrations (Figure 1E), mRNA expression of APP processing enzymes (BACE1 and 2; PS1 and 2) (Figure 1F) or levels of APP cleavage products (Figure 1G).”
Quote in the paperSubstantial claim- Rests on an assumption: The CRND8 mouse model of amyloid deposition is relevant to human Alzheimer's disease.
- Study design and conductown data
Microglia density in non-AD/CX3CR1 mutant mice did not differ between genotypes in the brain region analyzed.
“To control for possible differences in microglia density between CX3CR1 genotypes in the absence of AD pathology, we measured the density of microglia in non-AD/CX3CR1 mutant mice which did not differ between genotypes in the brain region analyzed.”
Quote in the paperSubstantial claim - Premisecitation
Deficits in microglia accumulations can accelerate amyloid deposition.
“deficits in microglia accumulations can accelerate amyloid deposition (El Khoury et al., 2007).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites El Khoury et al., 2007 source
- Study design and conductown data
In separate culture preparations containing only CX3CR1−/− microglia, 100% of IBA1-positive microglia were GFP positive.
“In separate culture preparations containing only CX3CR1−/− microglia we determined that 100% of IBA1-positive microglia were GFP positive.”
Quote in the paperSubstantial claim - Interpretationreasoning
The increased microglia number and proliferation likely contributed to an overall greater phagocytic capacity.
“Furthermore, CX3CR1 deficient mice had an increased number of microglia around individual plaques due to higher proliferative rates, which likely contributed to an overall greater phagocytic capacity.”
Quote in the paperSubstantial claim - Interpretationown data
Microglia can regulate brain Aβ levels and plaque deposition via selective protofibrillar Aβ phagocytosis.
“Our results demonstrate that microglia can regulate brain Aβ levels and plaque deposition via selective protofibrillar Aβ phagocytosis.”
Quote in the paperSubstantial claim- Rests on an assumption: The CRND8 mouse model of amyloid deposition is relevant to human Alzheimer's disease.
- Rests on an assumption: Fluorescently labeled Aβ42 (HiLyte-555) behaves like endogenous Aβ42 in binding, stability, and phagocytosis.
- Rests on an assumption: The absence of intracellular Thioflavin-S labeling indicates lack of phagocytosis of fibrillar amyloid rather than rapid degradation or masking of the label.
- Study design and conductown data
IBA1 has 100% colocalization with GFP-labeled cells in the brain parenchyma of CX3CR1 knock in mice.
“Furthermore, IBA1 has a 100% colocalization with GFP-labeled cells in the brain parenchyma of CX3CR1 knock in mice.”
Quote in the paperSubstantial claim - Interpretationcitation
Unbound Aβ42 was rapidly cleared possibly through the blood brain barrier.
“However, non-plaque areas immediately adjacent demonstrated very low fluorescence levels (Figure 3A) suggesting that unbound Aβ42 was rapidly cleared possibly through the blood brain barrier (DeMattos et al., 2002).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites DeMattos et al., 2002 source
- Rests on an assumption: Fluorescently labeled Aβ42 (HiLyte-555) behaves like endogenous Aβ42 in binding, stability, and phagocytosis.
- Interpretationown data
Soluble Aβ42 has a very high affinity for fibrillar amyloid within plaques.
“During imaging, we observed very rapid binding of Aβ42 (within minutes) to preexisting amyloid plaques (Figure 3A) suggesting a very high affinity of soluble Aβ42 for fibrillar amyloid within plaques.”
Quote in the paperSubstantial claim- Rests on an assumption: Fluorescently labeled Aβ42 (HiLyte-555) behaves like endogenous Aβ42 in binding, stability, and phagocytosis.
- Study design and conductreasoning
Minor differences in the proportion of microglia of each genotype do not affect the final results of the phagocytosis assay.
“Minor differences in the proportion of microglia of each genotype do not affect the final results of the phagocytosis assay given that in a mixture of cells there is equal likelihood for each individual cell regardless of its genotype to be exposed to Fluor 555-Aβ42 or microspheres.”
Quote in the paperSubstantial claim - Interpretationreasoning
Reducing microglia activation or phagocytosis could have deleterious effects in AD.
“In the case of CX3CR1, our results indicate that reducing microglia activation or phagocytosis could have deleterious effects in AD.”
Quote in the paperSubstantial claim - Interpretationown data
CX3CR1 may also exert direct effects on microglia phagocytosis.
“On the other hand, our experiment showing a rapid increase in phagocytic ability after incubation with anti-CX3CR1 neutralizing antibody suggests that CX3CR1 may also exert direct effects on microglia phagocytosis.”
Quote in the paperSubstantial claim - Interpretationown data
Increased proliferation rates around plaques are likely to explain the greater number of plaque-associated microglia in CX3CR1 deficient mice.
“Thus increased proliferation rates around plaques are likely to explain the greater number of plaque associated microglia in CX3CR1 deficient mice.”
Quote in the paperSubstantial claim - Interpretationown data
Differences in Aβ within microglia are not likely due to intracellular degradation but rather uptake differences.
“The fact that microsphere phagocytosis was increased demonstrates that differences in Aβ within microglia are not likely due to intracellular degradation but rather uptake differences.”
Quote in the paperSubstantial claim - Interpretationown data
Plaque-associated microglia do not exert a significant neuroprotective or neurotoxic bystander effect.
“This suggests that plaque-associated microglia do not exert a significant neuroprotective or neurotoxic “bystander” effect.”
Quote in the paperSubstantial claim - Interpretationown data
Many early Aβ deposits outside microglia are likely located in the extracellular space.
“Many of these early Aβ deposits outside of microglia were likely to be located in the extracellular space given that they did not colocalize with astrocytes either (Figure 4F and Supplementary Figure 1).”
Quote in the paperNot a substantial claim - Interpretationown data
CX3CR1−/− microglia have an overall enhanced phagocytic activity.
“We found that CX3CR1−/− microglia had a greater capacity to uptake both Aβ peptides and microspheres suggesting an overall enhanced phagocytic activity.”
Quote in the paperSubstantial claim - Interpretationown data
With CX3CR1 deficiency, microglia proliferation near plaques is increased leading to a greater density.
“In addition, we also found that with CX3CR1 deficiency, microglia proliferation near plaques was increased leading to a greater density.”
Quote in the paperNot a substantial claim - Interpretationown data
The newly formed Aβ deposits are being phagocytosed by microglia.
“Concurrent with the increase in fluorescence inside microglia, at day 16 there was a large decrease in the number and intensity of fluorescent aggregates outside microglia (Figure 4F) suggesting that these newly formed Aβ deposits were being phagocytosed.”
Quote in the paperSubstantial claim - Interpretationown data
Microglia play an important role in regulating brain amyloid levels and deposition.
“This demonstrates that microglia play an important role in regulating brain amyloid levels and deposition.”
Quote in the paperSubstantial claim- Rests on an assumption: CX3CR1 is specifically expressed in microglia in the brain.
- Interpretationown data
CX3CR1−/− microglia have an increased capacity to phagocytose endogenously produced amyloid.
“We found a significantly increased A11 and 4G8 immunofluorescence in phagolysosomes from CRND8/CX3CR1−/− mice compared to wild-type littermates, suggesting that CX3CR1−/− microglia have an increased capacity to phagocytose endogenously produced amyloid.”
Quote in the paperSubstantial claim - Interpretationown data
Reduction of CX3CR1 activity rapidly and specifically modulates phagocytosis.
“Pre incubation with anti-CX3CR1 neutralizing antibody 2 hours prior to the phagocytosis assay led to increased microsphere phagocytosis in CX3CR1+/+ microglia but not those lacking CX3CR1 (Figure 6E) demonstrating rapid and specific modulation of phagocytosis by the reduction of CX3CR1 activity.”
Quote in the paperSubstantial claim - Interpretationown data
The increased phagocytic capacity is not specific to amyloid but a general property of CX3CR1−/− microglia.
“It also indicates that the increased phagocytic capacity is not specific to amyloid but a general property of CX3CR1−/− microglia.”
Quote in the paperSubstantial claim - Interpretationreasoning
Given that CX3CR1 deficient mice have fewer plaques, it is likely that the overall pathological burden is diminished.
“However, given that CX3CR1 deficient mice have fewer plaques, it is likely that the overall pathological burden is diminished.”
Quote in the paperNot a substantial claim - Interpretationown data
These Aβ42(HiLyte)-555 deposits are composed of material in a protofibrillar Aβ conformation.
“Virtually none of these Aβ42(HiLyte)-555 accumulations co-labeled with TS (Figures 4B, D) suggesting that these deposits were composed of material in a protofibrillar Aβ conformation.”
Quote in the paperSubstantial claim
- May combine two claims. 20
- Classified as probably not a substantial claim. 16
May combine two claims.
PremisecitationCX3CR1 is selectively expressed in microglia and modulates microglial activity in response to fractalkine.
“The chemokine receptor CX3CR1 is selectively expressed in microglia and is thought to modulate their activity.”
- Also stated in: § INTRODUCTION · plain
“In the brain, this receptor is exclusively expressed in microglia and selectively modulates microglial activity in response to its ligand the chemokine fractalkine (Harrison et al., 1998).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Harrison et al., 1998 source
- Also stated in: § INTRODUCTION · plain
Classified as probably not a substantial claim.
PremisecitationMicroglia have been shown to be capable of phagocytosis of amyloid fibrils.
“Microglia have been shown to be capable of phagocytosis of amyloid fibrils (2)”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [2] source
The Results and Discussion passages address neutrophil chemokine receptors and migration during sepsis, not microglia or amyloid fibrils. Searches for microglial phagocytosis and amyloid-fibril uptake found no passage in our copy addressing the claim. (LLM, conf=0.76)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationConflicting evidence suggests either neurotoxic or neuroprotective effects of CX3CR1 deletion in various disease models.
“Conflicting evidence in the literature suggests either neurotoxic or neuroprotective effects of CX3CR1 deletion in various disease models (Cardona et al., 2006; Fuhrmann et al., 2010).”
Quote in the paperNot a substantial claim1 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationPrevious in vivo results range from showing that microglia are effective at phagocytosis of fibrillar amyloid to suggesting that microglia play no role in the control of amyloid deposition.
“Previous in vivo results range from showing that microglia are effective at phagocytosis of fibrillar amyloid (Frautschy et al., 1991; Bacskai et al., 2002; Bolmont et al., 2008) to suggesting that microglia play no role in the control of amyloid deposition (Grathwohl et al., 2009).”
Quote in the paperNot a substantial claim3 of 3 sources checked- cites Frautschy et al., 1991 source
The indexed Abstract describes neuronal responses to amyloid cores injected into rat brain, but does not report microglial phagocytosis. Searches for microglia and phagocytosis returned only the abstract and references; the available indexed text does not establish the finding attributed to Frautschy et al. (LLM, conf=0.72)
Experimental — accuracy not yet measured - cites Bacskai et al., 2002 source
The Results report in vivo clearance of dense-core amyloid plaques after antibody treatment, and the Discussion treats microglial phagocytosis as a possible clearance mechanism. But the paper attributes direct evidence of microglial phagocytosis to ex vivo work; its own in vivo experiments also found effective Fc-independent clearance. It therefore does not show that microglia phagocytosed fibrillar amyloid in vivo. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites Grathwohl et al., 2009 source
May combine two claims.
Interpretationown dataMicroglia exhibit an increasing capacity for Aβ phagocytosis as Aβ adopts protofibrillar conformations but fail to phagocytose fibrillar deposits in vivo.
“Thus, the long-term persistence of methoxy-XO4 and Aβ42 (HiLyte)-555 plaque labeling coupled with the absence of TS label inside microglia strongly suggests that little phagocytosis of fibrillar amyloid takes place in vivo.”
- Also stated in: § Microglia are effective at phagocytosis of protofibrillar amyloid in vivo · hedged
“Together, these data indicate that microglia exhibit an increasing capacity for Aβ phagocytosis as it gradually adopts protofibrillar conformations but fail to phagocytose fibrillar deposits that have adopted a β-pleated sheet conformation.”
- Also stated in: § DISCUSSION · plain
“However, in contrast to recent imaging studies (Bolmont et al., 2008) we found that microglia, while highly effective at phagocytosis of oligomeric and protofibrillar Aβ, were incapable of removing fibrillar amyloid from preexisting plaques in vivo.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Bolmont et al., 2008 source
The Discussion (page unavailable) proposes that microglia may phagocytose protofibrils at plaque edges, but does not report increasing phagocytic capacity as Aβ changes conformation. It also says further study is needed to determine whether the material taken up is soluble or fibrillar Aβ, so it does not establish that microglia fail to phagocytose fibrillar deposits in vivo. (LLM, conf=0.84)
Experimental — accuracy not yet measured
- Also stated in: § Microglia are effective at phagocytosis of protofibrillar amyloid in vivo · hedged
Classified as probably not a substantial claim. May combine two claims.
PremisecitationIt remains unclear to what extent microglia are capable of removing amyloid from pre-existing fibrillar congophilic plaques or of preventing the deposition of smaller protofibrillar Aβ aggregates.
“it remains unclear to what extent microglia are capable of removing amyloid from pre-existing fibrillar congophilic plaques (Stalder et al., 2001) or of preventing the deposition of smaller protofibrillar Aβ aggregates (Grathwohl et al., 2009).”
Quote in the paperSubstantial claim1 of 2 sources checked- cites Stalder et al., 2001 source
- cites Grathwohl et al., 2009 source
The citation to Grathwohl et al. attaches to the claim about preventing deposition of smaller protofibrillar Aβ aggregates, not to the preceding claim about removing pre-existing plaques. In the Introduction (page unavailable), the paper reports that microglial ablation did not prevent plaque formation or change the extent of Aβ deposition in APP mouse models. It does not specifically assess smaller protofibrillar aggregates, so it supports the broader uncertainty about microglia and deposition but not that specific form. (LLM, conf=0.82)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationA11 and 4G8 antibodies detect oligomeric and other protofibrillar conformations respectively.
“We obtained high resolution confocal images of brain slices from CRND8 mice stained with A11 and 4G8 antibodies, which detect oligomeric and other protofibrillar conformations respectively (Lesné et al., 2006; Kayed et al., 2007).”
Quote in the paperSubstantial claim1 of 2 sources checked- cites Lesné et al., 2006 source
- cites Kayed et al., 2007 source
The Background and Results (pages not provided) support A11 as a detector of prefibrillar oligomers. But the Results report that 4G8 reacts with both fibrillar and prefibrillar samples, including monomer-sized material; they do not support describing it as a detector of a distinct protofibrillar conformation. (LLM, conf=0.90)
Experimental — accuracy not yet measured
May combine two claims.
Findingown dataThere was no significant difference between CX3CR1 genotypes in APP concentrations, mRNA expression of APP processing enzymes (BACE1 and 2; PS1 and 2), or levels of APP cleavage products.
“there was no significant difference in amyloid precursor protein (APP) concentrations (Figure 1E), mRNA expression of APP processing enzymes (BACE1 and 2; PS1 and 2) (Figure 1F) or levels of APP cleavage products (Figure 1G).”
Quote in the paperSubstantial claim- Rests on an assumption: The CRND8 mouse model of amyloid deposition is relevant to human Alzheimer's disease.
May combine two claims.
Findingown dataMicroglia cell bodies can remain stable over months, and no significant difference in stability between mice of different CX3CR1 genotypes was observed.
“Microglia cell bodies however, can remain stable over months (Supplementary figure 4) but no significant difference in stability between mice of different CX3CR1 genotypes was observed (Figures 7E, F).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataDeletion of CX3CR1 leads to a significant reduction in the total levels of brain Aβ and in the number of amyloid plaques in a mouse model of AD.
“We show that deletion of the fractalkine receptor CX3CR1, which in the brain is specifically expressed in microglia, leads to a significant reduction in the total levels of brain Aβ and in the number of amyloid plaques in a mouse model of AD.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataNon-plaque areas show substantially lower overall proliferation rates and no significant differences between CX3CR1 genotypes.
“Interestingly, we found that the overall proportion of microglia that were BrdU-labeled was significantly greater in CRND8/CX3CR1−/− mice than in CRND8/CX3CR1+/+ littermates (Figure 7C, D), while non-plaque areas showed substantially lower overall proliferation rates and no significant differences between genotypes (Figure 7D).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataPre-incubation with anti-CX3CR1 neutralizing antibody increases microsphere phagocytosis in CX3CR1+/+ microglia but not in CX3CR1−/− microglia.
“Pre incubation with anti-CX3CR1 neutralizing antibody 2 hours prior to the phagocytosis assay led to increased microsphere phagocytosis in CX3CR1+/+ microglia but not those lacking CX3CR1 (Figure 6E) demonstrating rapid and specific modulation of phagocytosis by the reduction of CX3CR1 activity.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenResults were validated by manual counting in a subset of stacks.
“Results were validated by manual counting in a subset of stacks.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductreasoningMicroglia density around plaques was quantified in blindly selected plaques of the same average size to eliminate size as a variable.
“Microglia density around plaques was quantified in blindly selected plaques of the same average size to eliminate size as a variable which can lead to differences in microglia number unrelated to the CX3CR1 genotype..”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisereasoningIt is not clear how or to what extent microglia control brain amyloid levels or deposition.
“Thus, it is not clear how or to what extent microglia control brain amyloid levels or deposition.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataCX3CR1 deletion was associated with increased phagocytic ability which led to greater amyloid content within microglial phagolysosomes.
“CX3CR1 deletion was associated with increased phagocytic ability which led to greater amyloid content within microglial phagolysosomes.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataMicroglia play an important role in selective phagocytosis of oligomeric and protofibrillar Aβ but not of preexisting congophilic amyloid plaques.
“Thus, our data demonstrate that microglia play an important role in selective phagocytosis of oligomeric and protofibrillar Aβ but not of preexisting congophilic amyloid plaques.”
Quote in the paperSubstantial claim- Rests on an assumption: The absence of intracellular Thioflavin-S labeling indicates lack of phagocytosis of fibrillar amyloid rather than rapid degradation or masking of the label.
Classified as probably not a substantial claim.
Study design and conductnone givenAll images were obtained with standardized parameters of laser intensity, gain and pinhole size.
“All images were obtained with standardized parameters of laser intensity, gain and pinhole size.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataCX3CR1 deletion increased microglia proliferation and numbers specifically around plaques, which coupled with increased phagocytic ability, resulted in decreased brain amyloid levels and deposition.
“CX3CR1 deletion increased microglia proliferation and numbers specifically around plaques, which coupled with their increased phagocytic ability, resulted in decreased brain amyloid levels and deposition.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductreasoningIBA1 labels all brain microglia but cannot differentiate them from infiltrating macrophages.
“Thus IBA1 labels all brain microglia but cannot differentiate them from infiltrating macrophages given that macrophages also label with IBA1.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAll other experiments including quantification of Aβ within microglia and in vivo imaging were done in mixed gender mice but with equal gender distribution on each experimental group.
“All other experiments including quantification of Aβ within microglia and in vivo imaging experiments were done in mixed gender mice but with equal gender distribution on each experimental group.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenA subset of images was counted manually by an unbiased individual to corroborate the accuracy of automated counting.
“A subset of images was counted manually by an unbiased individual to corroborate the accuracy of our automated counting.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductnone givenConfocal images of plaques selected for similar size, location and cortical layer were obtained with standardized laser intensity, gain and pinhole sizes to allow inter-animal comparisons.
“Confocal images of plaques selected for their similar size, location and cortical layer were obtained for quantitative imaging using an Olympus FV10i Confocal Microscope (60X objective N.A. 1.2). Image z-stacks were taken with standardized laser intensity, gain and pinhole sizes to allow inter-animal comparisons.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningIncreased fractalkine signaling in aging could in theory restrain microglia and predispose individuals to amyloid deposition and toxicity.
“Increased fractalkine signaling in aging could in theory restrain microglia and predispose individuals to amyloid deposition and toxicity.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductnone givenTechnical limitations of in vivo imaging make it unfeasible to quantify microglia cell body dynamics over longer intervals with sufficient precision.
“However, technical limitations of in vivo imaging make it unfeasible to quantify microglia cell body dynamics over longer intervals with sufficient precision.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningAblation of microglia is likely to induce marked astrocyte activation and could turn astrocytes into more effective phagocytes that compensate for the loss of microglia, explaining the apparent lack of effect of microglia ablation on Aβ levels.
“Ablation is likely to induce marked astrocyte activation and could turn these cells into much more effective phagocytes which could compensate for the loss of microglia and thus explain the apparent lack of effect of microglia ablation on Aβ levels.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationcitationOngoing microglial phagocytosis around growing fibrillar deposits could reduce levels of oligomeric and protofibrillar Aβ, which may change the equilibrium between monomers, oligomers and fibrils, altering nucleation-dependent polymerization that leads to fibrillar plaque formation.
“Ongoing microglial phagocytosis around growing fibrillar deposits could reduce levels of oligomeric and protofibrillar Aβ, which may change the equilibrium between monomers, oligomers and fibrils, altering the process of nucleation-dependent polymerization that leads to fibrillar plaque formation (Harper and Lansbury Jr., 1997; Walsh et al., 1999).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Harper and Lansbury Jr., 1997 source
- cites Walsh et al., 1999
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
InterpretationcitationMicroglia activation is not an all-or-none process and its net effect may depend on the particular pathological scenario.
“Thus it appears that microglia activation is not an all or none process and its net effect may depend on the particular pathological scenario (Hanisch and Kettenmann, 2007).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Hanisch and Kettenmann, 2007 source
Probably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningSubtle variations in microglia recruitment/retention could contribute to the observed disparities in microglia number around plaques.
“Thus we cannot rule out that subtle variations in microglia recruitment/retention could contribute to the observed disparities in microglia number around plaques.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataCX3CR1 deficiency has neither neuroprotective nor neurotoxic effects around individual plaques at least in this model of Alzheimer's-like pathology.
“Thus it appears that CX3CR1 deficiency has neither neuroprotective nor neurotoxic effects around individual plaques at least in this model of Alzheimer’s-like pathology.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningThe main role played by microglia is likely to ameliorate the formation of new fibrillar plaques rather than to remove preexisting ones, with the most critical effect likely being at the earliest stages of plaque deposition.
“Thus, it is likely that the main role played by microglia is to ameliorate the formation of new fibrillar plaques rather than to remove preexisting ones, with the most critical effect likely being at the earliest stages of plaque deposition.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningWe cannot rule out that some of the effects we observed are at least partly due to peripheral macrophages entering the brain.
“Thus we cannot rule out that some of the effects we observed are at least partly due to peripheral macrophages entering the brain.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataThe effect of CX3CR1 deletion on brain amyloid is mediated by a general enhancement of microglia phagocytic ability as demonstrated both in vitro and in vivo.
“The effect of CX3CR1 deletion on brain amyloid was mediated by a general enhancement of microglia phagocytic ability as demonstrated both in vitro and in vivo.”
Quote in the paperSubstantial claim- The authors state this as an assumption: The disparity in Aβ uptake between CX3CR1 genotypes is mostly due to differential phagocytic capacity rather than macropinocytosis.
- Rests on an assumption: CX3CR1 is specifically expressed in microglia in the brain.
The paper relies on this without support.
The CRND8 mouse model of amyloid deposition is relevant to human Alzheimer's disease.
“we crossbred mice lacking CX3CR1 with the Alzheimer’s mouse model CRND8”
“CX3CR1−/− mice were crossbred with transgenic mice (CRND8) harboring the human amyloid precursor protein gene with the Indiana and Swedish mutations (Chishti et al., 2001).”
The paper relies on this without support.
Fluorescently labeled Aβ42 (HiLyte-555) behaves like endogenous Aβ42 in binding, stability, and phagocytosis.
“we developed a method for subarachnoid infusion of fluorescently tagged Aβ peptides”
“Aβ42 (HiLyte)-555 was being infused”
The paper relies on this without support.
In vivo two-photon imaging through a thinned skull does not alter microglial phagocytic behavior or plaque stability.
“GFP-labeled microglia and Methoxy-X04 (MX04) labeled plaques were imaged through a thinned skull preparation as previously described (Grutzendler et al., 2002).”
The paper relies on this without support.
The absence of intracellular Thioflavin-S labeling indicates lack of phagocytosis of fibrillar amyloid rather than rapid degradation or masking of the label.
“Quantification of TS fluorescence within IBA1-immunolabeled cells revealed absence of any intracellular TS labeling (Figure 2C, D) regardless of the CX3CR1 genotype (Figure 2D).”
“we found complete stability of the label at least over this 90 day interval (Figure 3B, C).”
The authors state this as an assumption.
The disparity in Aβ uptake between CX3CR1 genotypes is mostly due to differential phagocytic capacity rather than macropinocytosis.
“However, given that CX3CR1 deletion is able to modulate phagocytosis of polystyrene microspheres, we assume that the disparity in Aβ uptake between genotypes is mostly due to differential phagocytic capacity rather than macropinocytosis.”
The paper relies on this without support.
CX3CR1 is specifically expressed in microglia in the brain.
“We show that deletion of the fractalkine receptor CX3CR1, which in the brain is specifically expressed in microglia, leads to a significant reduction in the total levels of brain Aβ and in the number of amyloid plaques in a mouse model of AD.”
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?
Microglia engulf and degrade Aβ.
“Microglia engulf and degrade Aβ74,75”
From Amyloid-β induces lipid droplet-mediated microglial dysfunction via the enzyme DGAT2 in Alzheimer’s disease (2025) · cites this paper as [74]
The Results (page unavailable) show that microglia phagocytose oligomeric and protofibrillar Aβ, supporting “engulf.” The same passage says this material “may be targeted for degradation” because it is found in phagolysosomes; it does not establish degradation as a fact. The Discussion also reports that microglia could not remove fibrillar amyloid from preexisting plaques in vivo. (LLM, conf=0.88)
Experimental — accuracy not yet measuredTargeting 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.”
From Heterozygous CX3CR1 Deficiency in Microglia Restores Neuronal β-Amyloid Clearance Pathways and Slows Progression of Alzheimer's Like-Disease in PS1-APP Mice (2019) · cites this paper as [17]
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).”
From Heterozygous CX3CR1 Deficiency in Microglia Restores Neuronal β-Amyloid Clearance Pathways and Slows Progression of Alzheimer's Like-Disease in PS1-APP Mice (2019) · cites this paper as [17]
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).”
From Heterozygous CX3CR1 Deficiency in Microglia Restores Neuronal β-Amyloid Clearance Pathways and Slows Progression of Alzheimer's Like-Disease in PS1-APP Mice (2019) · cites this paper as [17]
The efficiency of individual phagocytic processes can be dependent on experimental conditions.
“although it is important to note that the efficiency of individual phagocytic processes can be dependent on experimental conditions65–67.”
From Transcriptional signature in microglia associated with Aβ plaque phagocytosis (2021) · cites this paper as [67]
Deletion of CX3CR1 or depression of the CX3CL1/CX3CR1 axis reduces Aβ deposition but exacerbates tau pathology, such as increased phosphorylation and aggregation of tau, and this is associated with worsened behavioral and cognitive impairments.
“Deletion of CX3CR1 or depression of the CX3CL1/CX3CR1 axis reduces Aβ deposition [130–132] but exacerbates tau pathology, such as increased phosphorylation and aggregation of tau, and this is associated with worsened behavioral and cognitive impairments [132–137] (Fig. 1).”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [130]
A reduction in plaque load was observed with Cx3cr1 knockout in amyloid models.
“whereas a reduction in plaque load was observed with Cx3cr1 knockout in amyloid models (Lee et al., 2010; Liu et al., 2010)”
From Microglia in Alzheimer’s disease (2018) · cites this paper as Liu et al., 2010
In Alzheimer's disease, microglia cluster around beta-amyloid plaques, indicating an inability to clear beta-amyloid.
“In AD, microglia cluster around beta-amyloid plaques highlighting their inability to clear beta-amyloid (Hickman et al., 2008; Liu et al., 2010).”
From iPSC-derived human microglia-like cells to study neurological diseases (2017) · cites this paper as Liu et al., 2010
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.
Reported final synaptophysin band exceeds ten-band scheme
MinorTen consecutive 3-μm bands starting at 2-5 μm would end at 29-32 μm. The stated final band at 32-35 μm would be an eleventh band.
“Then, 10 donut-shaped selection bands of 3 μm width were created at 3 μm intervals, covering a 30 μm circular area out from the evened plaque edge.”
“with the first band nearly adjacent to the plaque (all pixels 2–5 μm from the thresholded plaque edge), and the last band about 30 um away from the plaque edge (all pixels 32–35 μm from the thresholded plaque edge).”
Different antibody pretreatment times
MinorThe methods specify a 30-minute pretreatment with CX3CR1-neutralizing antibody, but the results describe it as occurring 2 hours before the phagocytosis assay.
“pretreated with or without 10μg/ml CX3CR1 neutralizing antibody for 30min and then incubated for 2 hours”
“Pre incubation with anti-CX3CR1 neutralizing antibody 2 hours prior to the phagocytosis assay”
Cited works that were retracted
Works this paper cites that were later retracted, from the retraction notices publishers deposit. Major when the notice came out before this paper was published.
Cites a retracted work: 10.1038/nature04533
InfoThe cited work was retracted on 2024-06-24 (notice 10.1038/s41586-024-07691-8), not before this paper was published (2010-12-15).
Cited work 10.1038/nature04533 · retracted 2024-06-24 · notice 10.1038/s41586-024-07691-8 · this paper published 2010-12-15
“We obtained high-resolution confocal images of brain slices from CRND8 mice stained with A11 and 4G8 antibodies, which detect oligomeric and other protofibrillar conformations, respectively (Lesné et al., 2006; Kayed et al., 2007).”
Cites
1 retracted
RETRACTED ARTICLE: A specific amyloid-β protein assembly in the brain impairs memory
Lesné, S., Koh, M. T., Kotilinek, L., Kayed, R., Glabe, C. G., Yang, A., Gallagher, M., & Ashe, K. H. (2006) · Nature · doi:10.1038/nature04533 · Cited by 2,769 · cited 2× · see citing works
“We obtained high-resolution confocal images of brain slices from CRND8 mice stained with A11 and 4G8 antibodies, which detect oligomeric and other protofibrillar conformations, respectively (Lesné et al., 2006; Kayed et al., 2007).”
MethodRetractedMicroglia-mediated neurotoxicity: uncovering the molecular mechanisms
Block, M. L., Zecca, L., & Hong, J.-S. (2007) · Nature Reviews Neuroscience · doi:10.1038/nrn2038 · Cited by 4,110 · cited 4× · see citing works
“Microglia have been shown to exacerbate neuronal death mainly in acute and subacute injury models in which they are fully activated (Wu et al., 2000; Cardona et al., 2006; Block et al., 2007).”
BackgroundResultInfluentialATP mediates rapid microglial response to local brain injury in vivo
Davalos, D., Grutzendler, J., Yang, G., Kim, J. V., Zuo, Y., Jung, S., Littman, D. R., Dustin, M. L., & Gan, W.-B. (2005) · Nature Neuroscience · doi:10.1038/nn1472 · Cited by 3,913 · cited 1× · see citing works
“Microglia are the resident immune cells of the brain and can become activated by a variety of changes in its structural and biochemical integrity (Davalos et al., 2005; Hanisch and Kettenmann, 2007).”
BackgroundSelf-citationMicroglia: Active sensor and versatile effector cells in the normal and pathologic brain
Hanisch, U.-K., & Kettenmann, H. (2007) · Nature Neuroscience · doi:10.1038/nn1997 · Cited by 3,676 · cited 2× · see citing works
“Thus, it appears that microglia activation is not an all-or-none process and its net effect may depend on the particular pathological scenario (Hanisch and Kettenmann, 2007).”
BackgroundLambert, M. P., Barlow, A. K., Chromy, B. A., Edwards, C., Freed, R., Liosatos, M., Morgan, T. E., Rozovsky, I., Trommer, B., Viola, K. L., et al. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.11.6448 · Cited by 3,506 · cited 3× · see citing works
“This function may be critical in controlling A deposition as well as levels of potentially neurotoxic A oligomers (Lambert et al., 1998).”
BackgroundJung, S., Aliberti, J., Graemmel, P., Sunshine, M. J., Kreutzberg, G. W., Sher, A., & Littman, D. R. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.11.4106-4114.2000 · Cited by 2,632 · cited 2× · see citing works
“To address these questions, we investigated mice lacking the chemokine receptor CX3CR1 (Jung et al., 2000).”
BackgroundHarper, J. D., & Lansbury, P. T. (1997) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.66.1.385 · Cited by 1,652 · see citing works
Local self-renewal can sustain CNS microglia maintenance and function throughout adult life
Ajami, B., Bennett, J. L., Krieger, C., Tetzlaff, W., & Rossi, F. M. V. (2007) · Nature Neuroscience · doi:10.1038/nn2014 · Cited by 1,643 · cited 2× · see citing works
“Although currently it is thought that macrophages may normally not enter the brain in significant numbers in the absence of blood– brain barrier disruption (Ajami et al., 2007; Mildner et al., 2007), fractalkine/CX3CR1 signaling may also have chemotactic effects on macrophages (Imai et al., 1997).”
BackgroundControl of microglial neurotoxicity by the fractalkine receptor
Cardona, A. E., Pioro, E. P., Sasse, M. E., Kostenko, V., Cardona, S. M., Dijkstra, I. M., Huang, D., Kidd, G., Dombrowski, S., Dutta, R., et al. (2006) · Nature Neuroscience · doi:10.1038/nn1715 · Cited by 1,531 · cited 6× · see citing works
“Microglia have been shown to exacerbate neuronal death mainly in acute and subacute injury models in which they are fully activated (Wu et al., 2000; Cardona et al., 2006; Block et al., 2007).”
BackgroundInfluentialImai, T., Hieshima, K., Haskell, C. A., Baba, M., Nagira, M., Nishimura, M., Kakizaki, M., Takagi, S., Nomiyama, H., Schall, T. J., et al. (1997) · Cell · doi:10.1016/s0092-8674(00)80438-9 · Cited by 1,446 · cited 2× · see citing works
“, 2007), fractalkine/CX3CR1 signaling may also have chemotactic effects on macrophages (Imai et al., 1997).”
BackgroundSimard, A. R., Soulet, D., Gowing, G., Julien, J.-P., & Rivest, S. (2006) · Neuron · doi:10.1016/j.neuron.2006.01.022 · Cited by 1,265 · cited 2× · see citing works
“In addition to microglia, peripheral macrophages have been shown to be capable of A phagocytosis in AD models (Simard et al., 2006).”
BackgroundLong-term dendritic spine stability in the adult cortex
Grutzendler, J., Kasthuri, N., & Gan, W.-B. (2002) · Nature · doi:10.1038/nature01276 · Cited by 1,198 · cited 2× · see citing works
“GFP-labeled microglia and Methoxy-X04 (MX04)-labeled plaques were imaged through a thinned skull preparation as previously described (Grutzendler et al., 2002).”
MethodSelf-citationHarrison, J. K., Jiang, Y., Chen, S., Xia, Y., Maciejewski, D., McNamara, R. K., Streit, W. J., Salafranca, M. N., Adhikari, S., Thompson, D. A., et al. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.18.10896 · Cited by 1,176 · cited 3× · see citing works
“Our findings support the concept that fractalkine through its receptor CX3CR1 (Harrison et al., 1998) acts as a repressor of microglia activation (Cardona et al., 2006).”
BackgroundMicroglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions
Mildner, A., Schmidt, H., Nitsche, M., Merkler, D., Hanisch, U.-K., Mack, M., Heikenwalder, M., Brück, W., Priller, J., & Prinz, M. (2007) · Nature Neuroscience · doi:10.1038/nn2015 · Cited by 1,089 · cited 2× · see citing works
“Although currently it is thought that macrophages may normally not enter the brain in significant numbers in the absence of blood– brain barrier disruption (Ajami et al., 2007; Mildner et al., 2007), fractalkine/CX3CR1 signaling may also have chemotactic effects on macrophages (Imai et al., 1997).”
BackgroundAmyloid β-Protein Fibrillogenesis
Walsh, D. M., Hartley, D. M., Kusumoto, Y., Fezoui, Y., Condron, M. M., Lomakin, A., Benedek, G. B., Selkoe, D. J., & Teplow, D. B. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.36.25945 · Cited by 1,046 · cited 2× · see citing works
“Ongoing microglial phagocytosis around growing fibrillar deposits could reduce levels of oligomeric and protofibrillar Aβ, which may change the equilibrium between monomers, oligomers and fibrils, altering the process of nucleationdependent polymerization that leads to fibrillar plaque formation (Harper and Lansbury J…”
BackgroundChishti, M. A., Yang, D.-S., Janus, C., Phinney, A. L., Horne, P., Pearson, J., Strome, R., Zuker, N., Loukides, J., French, J., et al. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m100710200 · Cited by 955 · cited 1× · see citing works
“CX3CR1 / mice were crossbred with transgenic mice (CRND8) harboring the human amyloid precursor protein gene with the Indiana and Swedish mutations (Chishti et al., 2001).”
BackgroundEl Khoury, J., Toft, M., Hickman, S. E., Means, T. K., Terada, K., Geula, C., & Luster, A. D. (2007) · Nature Medicine · doi:10.1038/nm1555 · Cited by 915 · cited 1× · see citing works
“Microglia have been shown to be capable of phagocytosis of amyloid fibrils (Frautschy et al., 1991), and deficits in microglia accumulations can accelerate amyloid deposition (El Khoury et al., 2007).”
BackgroundKayed, R., Head, E., Sarsoza, F., Saing, T., Cotman, C. W., Necula, M., Margol, L., Wu, J., Breydo, L., Thompson, J. L., et al. (2007) · Molecular Neurodegeneration · doi:10.1186/1750-1326-2-18 · Cited by 773 · see citing works
CD14 and Toll-Like Receptors 2 and 4 Are Required for Fibrillar Aβ-Stimulated Microglial Activation
Reed-Geaghan, E. G., Savage, J. C., Hise, A. G., & Landreth, G. E. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.3158-09.2009 · Cited by 591 · cited 1× · see citing works
“Signal transduction pathways associated with these receptors are known to modulate phagocytosis (Tahara et al., 2006; Richard et al., 2008) and cytokine production (Reed-Geaghan et al., 2009) after amyloid exposure.”
BackgroundDeMattos, R. B., Bales, K. R., Cummins, D. J., Paul, S. M., & Holtzman, D. M. (2002) · Science · doi:10.1126/science.1067568 · Cited by 563 · cited 4× · see citing works
“However, little A 42(HiLyte)-555 was observed in areas outside of plaques in the first 12 h after infusion, likely because of rapid A efflux through the BBB. Beginning at 24 h, however, scattered fluorescent A deposits became evident (Fig.”
BackgroundInfluentialMicroglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer's disease
Fuhrmann, M., Bittner, T., Jung, C. K. E., Burgold, S., Page, R. M., Mitteregger, G., Haass, C., LaFerla, F. M., Kretzschmar, H., & Herms, J. (2010) · Nature Neuroscience · doi:10.1038/nn.2511 · Cited by 562 · cited 3× · see citing works
“…models of MPTP (1-methyl-4-phenyl-1,2,3,6tetrahydropyridine) toxicity and amyotrophic lateral sclerosis (Cardona et al., 2006), whereas CX3CR1 deficiency was neuroprotective in models of cerebral ischemia (Dénes et al., 2008) and mutant tau/APP-associated neurodegeneration (Fuhrmann et al., 2010).”
BackgroundDynamics of the Microglial/Amyloid Interaction Indicate a Role in Plaque Maintenance
Bolmont, T., Haiss, F., Eicke, D., Radde, R., Mathis, C. A., Klunk, W. E., Kohsaka, S., Jucker, M., & Calhoun, M. E. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.4814-07.2008 · Cited by 526 · cited 3× · see citing works
“Previous in vivo results range from showing that microglia are effective at phagocytosis of fibrillar amyloid (Frautschy et al., 1991; Bacskai et al., 2002; Bolmont et al., 2008) to suggesting that microglia play no role in the control of amyloid deposition (Grathwohl et al., 2009).”
BackgroundResultRole of toll-like receptor signalling in A uptake and clearance
Tahara, K., Kim, H.-D., Jin, J.-J., Maxwell, J. A., Li, L., & Fukuchi, K.-I. (2006) · Brain · doi:10.1093/brain/awl249 · Cited by 493 · cited 1× · see citing works
“Signal transduction pathways associated with these receptors are known to modulate phagocytosis (Tahara et al., 2006; Richard et al., 2008) and cytokine production (Reed-Geaghan et al., 2009) after amyloid exposure.”
BackgroundKoenigsknecht-Talboo, J., & Landreth, G. E. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.1808-05.2005 · Cited by 477 · cited 1× · see citing works
“Thus, CX3CR1 modulation of phagocytosis may involve the indirect effect of some proinflammatory cytokines that can attenuate phagocytosis (Koenigsknecht-Talboo and Landreth, 2005).”
BackgroundMicroglia Mediate the Clearance of Soluble Aβ through Fluid Phase Macropinocytosis
Mandrekar, S., Jiang, Q., Lee, C. Y. D., Koenigsknecht-Talboo, J., Holtzman, D. M., & Landreth, G. E. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.5572-08.2009 · Cited by 415 · cited 3× · see citing works
“macropinocytosis to clear Aβ (Mandrekar et al., 2009).”
BackgroundKlunk, W. E., Bacskai, B. J., Mathis, C. A., Kajdasz, S. T., McLellan, M. E., Frosch, M. P., Debnath, M. L., Holt, D. P., Wang, Y., & Hyman, B. T. (2002) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/61.9.797 · Cited by 412 · cited 2× · see citing works
“We first labeled plaques by intraperitoneal injection of the fluorescent amyloid-binding dye methoxy-XO4 (Klunk et al., 2002) 48 hours prior to the first imaging session and without relabeling on subsequent sessions.”
MethodFormation and maintenance of Alzheimer's disease β-amyloid plaques in the absence of microglia
Grathwohl, S. A., Kälin, R. E., Bolmont, T., Prokop, S., Winkelmann, G., Kaeser, S. A., Odenthal, J., Radde, R., Eldh, T., Gandy, S., et al. (2009) · Nature Neuroscience · doi:10.1038/nn.2432 · Cited by 401 · cited 5× · see citing works
“, 2008) to suggesting that microglia play no role in the control of amyloid deposition (Grathwohl et al., 2009).”
BackgroundResultInfluential(2008) · Archives of Neurology · doi:10.1001/archneur.2008.65.7.nct70006 · Cited by 387 · cited 2× · see citing works
“This may at least partly explain why recent attempts at prevention of AD with nonsteroidal antiinflammatory therapy have been unsuccessful or even counterproductive (Martin et al., 2008).”
BackgroundSalminen, A., Ojala, J. O., Kauppinen, A., Kaarniranta, K., & Suuronen, T. (2009) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2009.01.001 · Cited by 350 · cited 2× · see citing works
“A large number of pattern recognition cell surface receptors in microglia such as the Toll-like family, receptor for advanced glycation end-products (RAGE) and scavenger receptors have been implicated in the recognition of amyloid oligomers and fibrils (Salminen et al., 2009).”
BackgroundNon-Fc-Mediated Mechanisms Are Involved in Clearance of Amyloid-β<i>In Vivo</i>by Immunotherapy
Bacskai, B. J., Kajdasz, S. T., McLellan, M. E., Games, D., Seubert, P., Schenk, D., & Hyman, B. T. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-18-07873.2002 · Cited by 323 · cited 3× · see citing works
“Previous in vivo results range from showing that microglia are effective at phagocytosis of fibrillar amyloid (Frautschy et al., 1991; Bacskai et al., 2002; Bolmont et al., 2008) to suggesting that microglia play no role in the control of amyloid deposition (Grathwohl et al., 2009).”
BackgroundAlves-Filho, J. C., Freitas, A., Souto, F. O., Spiller, F., Paula-Neto, H., Silva, J. S., Gazzinelli, R. T., Teixeira, M. M., Ferreira, S. H., & Cunha, F. Q. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0900196106 · Cited by 318 · cited 2× · see citing works
“Furthermore, crosstalk can occur between chemokine and pattern recognition receptor signaling pathways leading to functional changes in phagocytes (Kishore et al., 2005; Alves-Filho et al., 2009).”
BackgroundFrackowiak, J., Wisniewski, H. M., Wegiel, J., Merz, G. S., Iqbal, K., & Wang, K. C. (1992) · Acta Neuropathologica · doi:10.1007/bf00227813 · Cited by 276 · cited 2× · see citing works
“However, at this early time point a substantial number of deposits were already observed inside microglia within vesicular compartments consistent with phagolysosomes(Frackowiak et al., 1992) (Figure 4A, C and supplementary movie 1).”
BackgroundDénes, Á., Ferenczi, S., Halász, J., Környei, Z., & Kovács, K. J. (2008) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2008.64 · Cited by 276 · cited 2× · see citing works
“…models of MPTP (1-methyl-4-phenyl-1,2,3,6tetrahydropyridine) toxicity and amyotrophic lateral sclerosis (Cardona et al., 2006), whereas CX3CR1 deficiency was neuroprotective in models of cerebral ischemia (Dénes et al., 2008) and mutant tau/APP-associated neurodegeneration (Fuhrmann et al., 2010).”
BackgroundRichard, K. L., Filali, M., Préfontaine, P., & Rivest, S. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.1146-08.2008 · Cited by 261 · cited 2× · see citing works
“Signal transduction pathways associated with these receptors are known to modulate phagocytosis (Tahara et al., 2006; Richard et al., 2008) and cytokine production (Reed-Geaghan et al.”
BackgroundEffects of injected Alzheimer beta-amyloid cores in rat brain.
Frautschy, S. A., Baird, A., & Cole, G. M. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.19.8362 · Cited by 254 · cited 3× · see citing works
“Previous in vivo results range from showing that microglia are effective at phagocytosis of fibrillar amyloid (Frautschy et al., 1991; Bacskai et al., 2002; Bolmont et al., 2008) to suggesting that microglia play no role in the control of amyloid deposition (Grathwohl et al., 2009).”
BackgroundIntrahippocampal LPS injections reduce Aβ load in APP+PS1 transgenic mice
DiCarlo, G. (2001) · Neurobiology of Aging · doi:10.1016/s0197-4580(01)00292-5 · Cited by 223 · see citing works
Frautschy, S. A., Cole, G. M., & Baird, A. (1992) · PubMed Central · Cited by 157 · see citing works
Stalder, M., Deller, T., Staufenbiel, M., & Jucker, M. (2001) · Neurobiology of Aging · doi:10.1016/s0197-4580(01)00209-3 · Cited by 118 · cited 2× · see citing works
“…been studied in great detail using in vivo models, and it remains unclear to what extent microglia are capable of removing amyloid from preexisting fibrillar congophilic plaques (Stalder et al., 2001) or of preventing the deposition of smaller protofibrillar A aggregates (Grathwohl et al., 2009).”
BackgroundKim, T., Lim, H. K., Lee, J. Y., Kim, D., Park, S., Lee, C., & Lee, C. (2008) · Neuroscience Letters · doi:10.1016/j.neulet.2008.03.019 · Cited by 115 · cited 2× · see citing works
“, 2003) and plasma levels of fractalkine can be increased in AD patients (Kim et al., 2008).”
BackgroundT Cell Chemokine Receptor Expression in Aging
Mo, R., Chen, J., Yin, H., Bueno-Cannizares, C., Misek, D. E., Lescure, P., Hanash, S., & Yung, R. L. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.170.2.895 · Cited by 108 · cited 2× · see citing works
“Expression of various chemokines has been shown to be increased in the aging brain (Mo et al., 2003) and plasma levels of fractalkine can be increased in AD patients (Kim et al.”
BackgroundBeta-amyloid activated microglia induce cell cycling and cell death in cultured cortical neurons
Wu, Q. (2000) · Neurobiology of Aging · doi:10.1016/s0197-4580(00)00219-0 · Cited by 93 · cited 2× · see citing works
“Microglia have been shown to exacerbate neuronal death mainly in acute and subacute injury models where they are fully activated (Wu et al., 2000; Cardona et al., 2006; Block et al., 2007).”
BackgroundSelective suppression of Toll‐like receptor 4 activation by chemokine receptor 4
Kishore, S. P., Bungum, M. K., Platt, J. L., et al. (2004) · FEBS Letters · doi:10.1016/j.febslet.2004.12.047 · Cited by 34 · cited 1× · see citing works
“Furthermore, cross talk can occur between chemokine and pattern recognition receptor signaling pathways leading to functional changes in phagocytes (Kishore et al., 2005; Alves-Filho et al., 2009).”
Background
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Microglia in Alzheimer’s disease
Hansen, D. V., Hanson, J. E., & Sheng, M. (2018) · Journal of Cell Biology · doi:10.1083/jcb.201709069 · Cited by 1,935 · see citing works
Microglia in neurodegeneration
Hickman, S., Izzy, S., Sen, P., Morsett, L., & El Khoury, J. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0242-x · Cited by 1,710 · see citing works
Disease-Associated Microglia: A Universal Immune Sensor of Neurodegeneration
Deczkowska, A., Keren-Shaul, H., Weiner, A., Colonna, M., Schwartz, M., & Amit, I. (2018) · Cell · doi:10.1016/j.cell.2018.05.003 · Cited by 1,474 · see citing works
iPSC-derived human microglia-like cells to study neurological diseases
Abud, E. M., Ramirez, R. N., Martinez, E. S., Healy, L. M., Nguyen, C. H. H., Newman, S. A., Yeromin, A. V., Scarfone, V. M., Marsh, S. E., Fimbres, C., et al. (2017) · Neuron · doi:10.1016/j.neuron.2017.03.042 · Cited by 1,154 · see citing works
“In AD, microglia cluster around beta-amyloid plaques highlighting their inability to clear beta-amyloid (Hickman et al., 2008, Liu et al., 2010).”
Microglia development and function
Nayak, D., Roth, T. L., & McGavern, D. B. (2014) · Annual Review of Immunology · doi:10.1146/annurev-immunol-032713-120240 · Cited by 1,154 · see citing works
Innate immunity in the central nervous system
Ransohoff, R. M., & Brown, M. A. (2012) · Journal of Clinical Investigation · doi:10.1172/jci58644 · Cited by 1,034 · see citing works
“CX3CR1-deficient CX3CR1-deficient mice show enhanced amyloid clearance in Alzheimer’s disease (AD) amyloid deposition models (64), consistent with beneficial activation of microglia (52, 63, 65, 66).”
Microglia-mediated neuroinflammation in neurodegenerative diseases
Subhramanyam, C. S., Wang, C., Hu, Q., & Dheen, S. T. (2019) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2019.05.004 · Cited by 875 · see citing works
Yuan, P., Condello, C., Keene, C. D., Wang, Y., Bird, T. D., Paul, S. M., Luo, W., Colonna, M., Baddeley, D., & Grutzendler, J. (2016) · Neuron · doi:10.1016/j.neuron.2016.05.003 · Cited by 817 · see citing works
“However, multiple recent lines of evidence indicate that microglia are ineffective at removing fibrillar Ab in vivo (Condello et al., 2011; Liu et al., 2010; Stalder et al., 2001).”
Self-citationMicroglia constitute a barrier that prevents neurotoxic protofibrillar Aβ42 hotspots around plaques
Condello, C., Yuan, P., Schain, A., & Grutzendler, J. (2015) · Nature Communications · doi:10.1038/ncomms7176 · Cited by 718 · see citing works
Self-citationHeterogeneity of CNS myeloid cells and their roles in neurodegeneration
Prinz, M., Priller, J., Sisodia, S. S., & Ransohoff, R. M. (2011) · Nature Neuroscience · doi:10.1038/nn.2923 · Cited by 674 · see citing works
CX3CR1 deficiency leads to impairment of hippocampal cognitive function and synaptic plasticity
Rogers, J. T., Morganti, J. M., Bachstetter, A. D., Hudson, C. E., Peters, M. M., Grimmig, B. A., Weeber, E. J., Bickford, P. C., & Gemma, C. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.3667-11.2011 · Cited by 624 · see citing works
“Furthermore, CX3CR1 / mice crossed with the AD mouse model CRND8 had lower brain levels of A 40 and A 42 and reduced amyloid deposits, which are related to increased microglia proliferation and phagocytosis (Liu et al., 2010).”
BackgroundJanus-faced microglia: beneficial and detrimental consequences of microglial phagocytosis
Sierra, A., Abiega, O., Shahraz, A., & Neumann, H. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00006 · Cited by 574 · see citing works
“The fractalkine receptor, a regulator of phagocytosis, has been found to contribute to the Aβ burden by some (Lee et al., 2010; Liu et al., 2010) but not others (Fuhrmann et al., 2010).”
BackgroundAmyloid-β-independent regulators of tau pathology in Alzheimer disease
van der Kant, R., Goldstein, L. S. B., & Ossenkoppele, R. (2020) · Nature reviews. Neuroscience · doi:10.1038/s41583-019-0240-3 · Cited by 580 · see citing works
Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation
Chen, Y., & Yu, Y. (2023) · Journal of Neuroinflammation · doi:10.1186/s12974-023-02853-3 · Cited by 516 · see citing works
Inflammation: the link between comorbidities, genetics, and Alzheimer’s disease
Newcombe, E. A., Camats-Perna, J., Silva, M. L., Valmas, N., Huat, T. J., & Medeiros, R. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1313-3 · Cited by 532 · see citing works
Krabbe, G., Halle, A., Matyash, V., Rinnenthal, J. L., Eom, G. D., Bernhardt, U., Miller, K. R., Prokop, S., Kettenmann, H., & Heppner, F. L. (2013) · PLoS ONE · doi:10.1371/journal.pone.0060921 · Cited by 478 · see citing works
Bidirectional Microglia–Neuron Communication in Health and Disease
Szepesi, Z., Manouchehrian, O., Bachiller, S., & Deierborg, T. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00323 · Cited by 459 · see citing works
“However, others have demonstrated that both APP-PS1/CX3CR1−/− and CRND8/CX3CR1−/− mice showed reduction in Aβ deposition with increased number of microglia (Lee et al., 2010; Liu et al., 2010).”
BackgroundThe contribution of neuroinflammation to amyloid toxicity in Alzheimer's disease
Minter, M. R., Taylor, J. M., & Crack, P. J. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13411 · Cited by 451 · see citing works
“CX3CR1 deficiency in multiple mouse models of AD has been shown to promote microglial phagocytosis of Ab, reducing plaque burden and neurotoxicity (Fuhrmann et al. 2010; Lee et al. 2010; Liu et al. 2010).”
BackgroundLucin, K. M., O’Brien, C. E., Bieri, G., Czirr, E., Mosher, K. I., Abbey, R. J., Mastroeni, D. F., Rogers, J., Spencer, B., Masliah, E., et al. (2013) · Neuron · doi:10.1016/j.neuron.2013.06.046 · Cited by 374 · see citing works
Factors regulating microglia activation
Kierdorf, K., & Prinz, M. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00044 · Cited by 360 · see citing works
“Nevertheless, several studies on the role of CX3CR1deficiency in animal models for Alzheimer’s disease (AD) revealed quite divergent results (Fuhrmann et al., 2010; Lee et al., 2010; Liu et al., 2010; Prinz et al., 2011).”
ResultTranscriptional signature in microglia associated with Aβ plaque phagocytosis
Grubman, A., Choo, X. Y., Chew, G., Ouyang, J. F., Sun, G., Croft, N. P., Rossello, F. J., Simmons, R., Buckberry, S., Landin, D. V., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-23111-1 · Cited by 357 · see citing works
Macrophages: An Inflammatory Link Between Angiogenesis and Lymphangiogenesis
Corliss, B. A., Azimi, M. S., Munson, J. M., Peirce, S. M., & Murfee, W. L. (2016) · Microcirculation · doi:10.1111/micc.12259 · Cited by 356 · see citing works
“A limitation with this approach, however, is that the radiation used to deplete stem cells in the bone marrow also inflicts whole body injury, causing increased vascular permeability [68,140] and other nonphysiologic behaviors [146,169].”
BackgroundLuo, R., Su, L.-Y., Li, G., Yang, J., Liu, Q., Yang, L.-X., Zhang, D.-F., Zhou, H., Xu, M., Fan, Y., et al. (2020) · Autophagy · doi:10.1080/15548627.2019.1596488 · Cited by 364 · see citing works
“[57] Liu Z, Condello C, Schain A, et al.”
BackgroundMicroglia, seen from the CX3CR1 angle
Wolf, Y., Yona, S., Kim, K.-W., & Jung, S. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00026 · Cited by 316 · see citing works
“…the CX3CR1−/− mice to CRND8 transgenic mice that harbor a gene encoding a mutant human amyloid precursor protein also resulted in reduced Aβ deposits, with the CX3CR1deficient microglia phagocytosing amyloid plaques and displaying higher proliferation rates in the plaque regions (Liu et al., 2010).”
BackgroundMicroglia in Health and Disease
Ransohoff, R. M., & Khoury, J. E. (2016) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a020560 · Cited by 303 · see citing works
Advances in developing novel therapeutic strategies for Alzheimer’s disease
Cao, J., Hou, J., Ping, J., & Cai, D. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0299-8 · Cited by 283 · see citing works
“Genetic deletion of the chemokine receptor CX3CR1 in microglia can also enhance formation of microglial barrier around amyloid plaques [212], and thereby reduce plaque load [214, 215].”
BackgroundLee, M., Lee, Y., Song, J., Lee, J., & Chang, S.-Y. (2018) · Immune Network · doi:10.4110/in.2018.18.e5 · Cited by 260 · see citing works
“In the brain, CX3CL1/CX3CR1 signaling can modulate the production of cytokines by microglia cells (8).”
BackgroundThe Impact of the CX3CL1/CX3CR1 Axis in Neurological Disorders
Pawelec, P., Ziemka‐Nałęcz, M., Sypecka, J., & Zalewska, T. (2020) · Cells · doi:10.3390/cells9102277 · Cited by 272 · see citing works
“Notably, despite the increased density of microglia, there was no effect of CX3CR1 deletion on the degree of neuronal and synaptic damage surrounding the plaques [93].”
BackgroundInfluentialCho, S.-H., Sun, B., Zhou, Y., Kauppinen, T. M., Halabisky, B., Wes, P., Ransohoff, R. M., & Gan, L. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.254268 · Cited by 268 · see citing works
Real-Time In Vivo Imaging Reveals the Ability of Monocytes to Clear Vascular Amyloid Beta
Michaud, J.-P., Bellavance, M.-A., Préfontaine, P., & Rivest, S. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.10.010 · Cited by 257 · see citing works
“Whether internalized Ab aggregates are degraded remains uncertain but many evidence support the capacity of monocytes/macrophages to eliminate Ab with much greater efficiency than microglia (Fiala et al., 2007; Liu et al., 2010; Majumdar et al., 2008; 2007; Simard et al., 2006).”
BackgroundCerbai, F., Lana, D., Nosi, D., Petkova-Kirova, P., Zecchi, S., Brothers, H. M., Wenk, G. L., & Giovannini, M. G. (2012) · PLoS ONE · doi:10.1371/journal.pone.0045250 · Cited by 251 · see citing works
The Ischemic Environment Drives Microglia and Macrophage Function
Fumagalli, S., Perego, C., Pischiutta, F., Zanier, E. R., & Simoni, M. G. D. (2015) · Frontiers in Neurology · doi:10.3389/fneur.2015.00081 · Cited by 245 · see citing works
“28 days Yes ↓ Aβ deposition, ↑ Aβ phagocytosis, ↑ microglia proliferation, = neuronal injury (198)”
Microglia in Brain Development, Homeostasis, and Neurodegeneration
Bohlen, C. J., Friedman, B. A., Dejanovic, B., & Sheng, M. (2019) · Annual Review of Genetics · doi:10.1146/annurev-genet-112618-043515 · Cited by 212 · see citing works
Microglia-neuron crosstalk: Signaling mechanism and control of synaptic transmission
Marinelli, S., Basilico, B., Marrone, M. C., & Ragozzino, D. (2019) · Seminars in Cell & Developmental Biology · doi:10.1016/j.semcdb.2019.05.017 · Cited by 233 · see citing works
Analyzing dendritic spine pathology in Alzheimer’s disease: Problems and opportunities
Dorostkar, M. M., Zou, C., Blazquez-Llorca, L., & Herms, J. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1449-5 · Cited by 235 · see citing works
Baik, S. H., Kang, S., Son, S. M., & Mook-Jung, I. (2016) · Glia · doi:10.1002/glia.23074 · Cited by 234 · see citing works
“It has been reported that microglia can take up and degrade fibrillary Ab by phagocytosis (Cho et al., 2014; Liu et al., 2010).”
BackgroundThe Role of Sex and Sex Hormones in Neurodegenerative Diseases
Vegeto, E., Villa, A. M., Torre, S. D., Crippa, V., Rusmini, P., Cristofani, R., Galbiati, M., Maggi, A. C., & Poletti, A. (2019) · Endocrine Reviews · doi:10.1210/endrev/bnz005 · Cited by 231 · see citing works
Microglia in Alzheimer's Disease: Exploring How Genetics and Phenotype Influence Risk
McQuade, A., & Blurton-Jones, M. (2019) · Journal of Molecular Biology · doi:10.1016/j.jmb.2019.01.045 · Cited by 244 · see citing works
Serrano-Pozo, A., Muzikansky, A., Gómez-Isla, T., Growdon, J. H., Betensky, R. A., Frosch, M. P., & Hyman, B. T. (2013) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e3182933788 · Cited by 226 · see citing works
“On the other hand, microglial responses to plaques may contribute to stabilizing plaque size, which remains relatively stable throughout the clinical course of the disease (22, 33), perhaps by effectively phagocytosing and degrading the smaller and more soluble AA species in the halo around dense-core plaques (59).”
Microglia contribute to the propagation of Aβ into unaffected brain tissue
d’Errico, P., Ziegler-Waldkirch, S., Aires, V., Hoffmann, P., Mezö, C., Erny, D., Monasor, L. S., Liebscher, S., Ravi, V. M., Joseph, K., et al. (2022) · Nature Neuroscience · doi:10.1038/s41593-021-00951-0 · Cited by 214 · see citing works
Modulating neurotoxicity through CX3CL1/CX3CR1 signaling
Limatola, C., & Ransohoff, R. M. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00229 · Cited by 210 · see citing works
“In Alzheimer’s disease (AD), CX3CL1/CX3CR1 blockade modulates microglia phagocytic activity in a way that markedly attenuates amyloid deposition (Lee et al., 2010; Liu et al., 2010).”
BackgroundImpact of Cytokines and Chemokines on Alzheimer’s Disease Neuropathological Hallmarks
Domingues, C., Silva, O. A. B. D. C. E., & Henriques, A. G. (2017) · Current Alzheimer Research · doi:10.2174/1567205014666170317113606 · Cited by 212 · see citing works
“Consistently, CX3CR1 receptor deficiency was previously shown to increase TAU phosphorylation [141] and to ameliorate Aβ levels and deposition [142, 143].”
Zabel, M. K., Zhao, L., Zhang, Y., Gonzalez, S. R., Ma, W., Wang, X., Fariss, R. N., & Wong, W. T. (2016) · Glia · doi:10.1002/glia.23016 · Cited by 210 · see citing works
“, 2011), and amyloid plaque clearance in Alzheimer’s disease models (Lee et al., 2010; Liu et al., 2010).”
BackgroundCX3CL1/CX3CR1 signaling targets for the treatment of neurodegenerative diseases
Subbarayan, M. S., Joly‐Amado, A., Bickford, P. C., & Nash, K. R. (2021) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2021.107989 · Cited by 204 · see citing works
Microglial immune checkpoint mechanisms
Deczkowska, A., Amit, I., & Schwartz, M. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0145-x · Cited by 185 · see citing works
Tang, Z., Gan, Y. X., Liu, Q., Yin, J., Liu, Q., Shi, J., & Shi, F. (2014) · Journal of Neuroinflammation · doi:10.1186/1742-2094-11-26 · Cited by 192 · see citing works
CX3CL1 Is Neuroprotective in Permanent Focal Cerebral Ischemia in Rodents
Cipriani, R., Villa, P., Chece, G., Lauro, C., Paladini, A., Micotti, E., Perego, C., Simoni, M. G. D., Fredholm, B. B., Eusebi, F., et al. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.3611-11.2011 · Cited by 189 · see citing works
“In different models of neuroinflammatory diseases, CX3CR1 deficiency correlated with enhanced microglia phagocytosis (Lee et al., 2010; Liu et al., 2010) and altered production of inflammatory cytokines (Cardona et al.”
BackgroundSex differences in microglial CX3CR1 signalling determine obesity susceptibility in mice
Dorfman, M. D., Krull, J. E., Douglass, J. D., Fasnacht, R. D., Lara-Lince, F., Meek, T. H., Shi, X., Damian, V. M., Hồng, N. T., Matsen, M. E., et al. (2017) · Nature Communications · doi:10.1038/ncomms14556 · Cited by 169 · see citing works
Young microglia restore amyloid plaque clearance of aged microglia
Daria, A., Colombo, A., Llovera, G., Hampel, H., Willem, M., Liesz, A., Haass, C., & Tahirovic, S. (2017) · The EMBO Journal · doi:10.15252/embj.201694591 · Cited by 174 · see citing works
“Several studies proposed that microglia/macrophages are involved in the clearance of A b (Rogers et al , 2002; Simard et al , 2006; El Khoury et al , 2007; Bolmont et al , 2008; Lee & Landreth, 2010; Liu et al , 2010; Krabbe et al , 2013).”
Functions of microglia in the central nervous system—beyond the immune response
Wake, H., Moorhouse, A. J., & Nabekura, J. (2011) · Neuron Glia Biology · doi:10.1017/s1740925x12000063 · Cited by 167 · see citing works
Bone Marrow Cell Recruitment to the Brain in the Absence of Irradiation or Parabiosis Bias
Kierdorf, K., Katzmarski, N., Haas, C. A., & Prinz, M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0058544 · Cited by 165 · see citing works
“affecting the integrity of the BBB [19,20], decreasing tight junction proteins [21] and inducing endothelial cell apoptosis [22].”
BackgroundDá Mesquita, S., Ferreira, A. C., Sousa, J. C., Correia-Neves, M., Sousa, N., & Marques, F. (2016) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2016.06.014 · Cited by 166 · see citing works
Systematic Review of the Neurobiological Relevance of Chemokines to Psychiatric Disorders
Stuart, M. J., Singhal, G., & Baune, B. T. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00357 · Cited by 163 · see citing works
Clearance of Amyloid-β Peptides By Microglia and Macrophages: the Issue of What, When and Where
Lai, A. Y., & McLaurin, J. (2012) · Future Neurology · doi:10.2217/fnl.12.6 · Cited by 161 · see citing works
TREM2 Function in Alzheimer’s Disease and Neurodegeneration
Ulrich, J. D., & Holtzman, D. M. (2016) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.5b00313 · Cited by 154 · see citing works
Microglia limit the expansion of β-amyloid plaques in a mouse model of Alzheimer’s disease
Zhao, R., Hu, W., Tsai, J., Li, W., & Gan, W.-B. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0188-6 · Cited by 151 · see citing works
Borrajo, A., Spuch, C., Penedo, M. A., Olivares, J. M., & Agís‐Balboa, R. C. (2020) · Annals of Medicine · doi:10.1080/07853890.2020.1814962 · Cited by 150 · see citing works
“Beta amyloid [29] and Tau protiens [30]—whose accu-”
BackgroundCXCR3 promotes plaque formation and behavioral deficits in an Alzheimer’s disease model
Krauthausen, M., Kummer, M. P., Zimmermann, J., Reyes-Irisarri, E., Terwel, D., Bulic, B., Heneka, M. T., & Müller, M. (2014) · Journal of Clinical Investigation · doi:10.1172/jci66771 · Cited by 147 · see citing works
Stress induced microglial activation contributes to depression
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Functional and structural damage of neurons by innate immune mechanisms during neurodegeneration
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Neuroinflammation and fractalkine signaling in Alzheimer’s disease
Finneran, D. J., & Nash, K. R. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1412-9 · Cited by 133 · see citing works
“Interestingly, from the Cx3cr1−/− studies described above, one may predict that the FKN over expression may worsen amyloid pathology [7, 9, 68].”
Brelstaff, J. H., Mason, M., Katsinelos, T., McEwan, W. A., Ghetti, B., Tolkovsky, A. M., & Spillantini, M. G. (2021) · Science Advances · doi:10.1126/sciadv.abg4980 · Cited by 135 · see citing works
“The switch from a pro-resolution phenotype to a hypophagocytic phenotype was suggested to represent a proinflammatory state that occurs when the microglia fail to digest and degrade engulfed, highly stable filamentous protein aggregates ( 45 , 46 ).”
The endocytic pathway in microglia during health, aging and Alzheimer’s disease
Solé-Domènech, S., Cruz, D. L., Capetillo-Zarate, E., & Maxfield, F. R. (2016) · Ageing Research Reviews · doi:10.1016/j.arr.2016.07.002 · Cited by 133 · see citing works
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Microglia-Mediated Neuroprotection, TREM2, and Alzheimer’s Disease: Evidence From Optical Imaging
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“However, these microglial processes are not optimally positioned to remove prefibrillar Ab because they are closely anchored to the perimeter of the compact plaque core (27) rather than at the site of the less compact plaque halo and under normal conditions have been shown to have a limited capacity for phagocytosis o…”
InfluentialSelf-citationCellular Stress Response and Immune Signaling in Retinal Ischemia–Reperfusion Injury
Minhas, G., Sharma, J. N., & Khan, N. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00444 · Cited by 130 · see citing works
“As is seen in the case of Alzheimer’s, where the activation of microglia helps in clearance of amyloid load and hence is beneficial (61, 62).”
BackgroundOpposing Effects of Membrane-Anchored CX3CL1 on Amyloid and Tau Pathologies via the p38 MAPK Pathway
Lee, S., Xu, G., Jay, T. R., Bhatta, S., Kim, K.-W., Jung, S., Landreth, G. E., Ransohoff, R. M., & Lamb, B. T. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.0853-14.2014 · Cited by 123 · see citing works
“In several transgenic mouse models of AD, CX3CR1 deficiency ameliorated A deposition by altering microglial activation and promoting microglial phagocytosis (Lee et al., 2010; Liu et al., 2010).”
BackgroundModulation of inflammation in transgenic models of Alzheimer’s disease
Birch, A. M., Katsouri, L., & Sastre, M. (2014) · Journal of Neuroinflammation · doi:10.1186/1742-2094-11-25 · Cited by 119 · see citing works
Tzeng, T.-T., Chen, C., Lee, L., Wan-Ping, C., Chung-Kuang, L., Shen, C., Chi-Ying, H. F., Chien-Chih, C., & Shiao, Y. (2016) · Journal of Biomedical Science · doi:10.1186/s12929-016-0266-z · Cited by 122 · see citing works
Furube, E., Kawai, S., Inagaki, H., Takagi, S., & Miyata, S. (2018) · Scientific Reports · doi:10.1038/s41598-018-20643-3 · Cited by 118 · see citing works
Inflammatory mechanisms in neurodegeneration
Nichols, M. R., St‐Pierre, M., Wendeln, A., Makoni, N. J., Gouwens, L. K., Garrad, E. C., Sohrabi, M., Neher, J. J., Tremblay, M., & Combs, C. K. (2019) · Journal of Neurochemistry · doi:10.1111/jnc.14674 · Cited by 122 · see citing works
“Grutzendler and colleagues demonstrated in an in vivo study that microglia were highly effective at protofibrillar Ab uptake but were incapable of phagocytosis of fibrillar congophilic Ab (Liu et al. 2010).”
BackgroundLee, D. C., Ruiz, C. R., Lebson, L. A., Selenica, M. B., Rizer, J., Hunt, J. B., Rojiani, R., Reid, P., Kammath, S., Nash, K. R., et al. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.12.014 · Cited by 119 · see citing works
“…on amyloid versus tau pathology is being observed, with microglial activation by lipopolysaccharide, fractalkine receptor deletion, or IL-1 overexpression benefiting amyloid pathology, yet exacerbating tau pathology (DiCarlo et al., 2001; Lee et al., 2010; Liu et al., 2010; Shaftel et al., 2007).”
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Genetic targeting of microglia
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Fractalkine in the nervous system: neuroprotective or neurotoxic molecule?
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Attenuation of β-Amyloid Deposition and Neurotoxicity by Chemogenetic Modulation of Neural Activity
Yuan, P., & Grutzendler, J. (2016) · Journal of Neuroscience · doi:10.1523/jneurosci.2531-15.2016 · Cited by 114 · see citing works
“Given that small plaques and diffuse plaques are likely to be the most recently formed (Liu et al., 2010; Condello et al., 2011), these data suggest that neural activity significantly influences the formation of new plaques but does not Figure 3.”
BackgroundSelf-citationCentral nervous system myeloid cells as drug targets: current status and translational challenges
Biber, K. P. H., Möller, T., Boddeke, E., & Prinz, M. (2015) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2015.14 · Cited by 111 · see citing works
Reduced microglial CX3CR1 expression delays neurofibromatosis‐1 glioma formation
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Time-dependent effects of CX3CR1 in a mouse model of mild traumatic brain injury
Febinger, H. Y., Thomasy, H. E., Pavlova, M. N., Ringgold, K. M., Barf, P. R., George, A. M., Grillo, J. N., Bachstetter, A. D., Garcia, J. A., Cardona, A. E., et al. (2015) · Journal of Neuroinflammation · doi:10.1186/s12974-015-0386-5 · Cited by 110 · see citing works
In vivo dynamics of innate immune sentinels in the CNS
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Cytokine-producing microglia have an altered beta-amyloid load in aged APP/PS1 Tg mice
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G Protein-Coupled Receptors (GPCRs) in Alzheimer’s Disease: A Focus on BACE1 Related GPCRs
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“AD is the most common neurodegenerative disorder afflicting around 24.0 million people worldwide, the morbidity rate of which rises dramatically as people get older (Erb et al., 2015).”
InfluentialHernandez, M. X., Jiang, S., Cole, T. A., Chu, S., Fonseca, M. I., Fang, M. J., Hohsfield, L. A., Torres, M. D., Green, K. N., Wetsel, R. A., et al. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0210-z · Cited by 101 · see citing works
<i>Cx3cr1-</i> deficient microglia exhibit a premature aging transcriptome
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“…in the acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson ’ s disease and in tauopathies such as frontotemporal dementia, but promotes amyloid clearance in models of amyloid β deposition (Cardona et al, 2006; Bhaskar et al, 2010; Lee et al, 2010; Liu et al, 2010).”
Prakash, P., Manchanda, P., Paouri, E., Bisht, K., Sharma, K., Rajpoot, J., Wendt, V., Hossain, A., Wijewardhane, P. R., Randolph, C. E., et al. (2025) · Immunity · doi:10.1016/j.immuni.2025.04.029 · Cited by 104 · see citing works
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Self-citationMulticolor time-stamp reveals the dynamics and toxicity of amyloid deposition
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Role of Chemokines in the Development and Progression of Alzheimer’s Disease
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From development to dysfunction: Microglia and the complement cascade in CNS homeostasis
Zabel, M. K., & Kirsch, W. M. (2013) · Ageing Research Reviews · doi:10.1016/j.arr.2013.02.001 · Cited by 95 · see citing works
Fate of microglia during HIV‐1 infection: From activation to senescence?
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“In the context of neurodegenerative diseases, microglial cells play essential roles in the clearance of beta amyloid (Ab) proteins (Liu et al., 2010), the accumulation of which correlates significantly with neurocognitive impairments.”
BackgroundMoutinho, M., Puntambekar, S. S., Tsai, A. P., Coronel, I., Lin, P. B., Casali, B. T., Martinez, P., Oblak, A. L., Lasagna-Reeves, C. A., Lamb, B. T., et al. (2022) · Science Translational Medicine · doi:10.1126/scitranslmed.abl7634 · Cited by 92 · see citing works
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“On one hand, the lack of CX3CR1 lead to beneficial effects in models of amyloidosis by causing a reduction in amyloid-b (Ab) deposition (Lee et al., 2010, 2014; Liu et al., 2010) and in a triple transgenicmouse harboring both tau and Ab mutations by preventing neuron loss (Fuhrmann et al., 2010).”
BackgroundThe Evolving Biology of Microglia in Alzheimer's Disease
Malm, T. M., Jay, T. R., & Landreth, G. E. (2015) · Neurotherapeutics · doi:10.1007/s13311-014-0316-8 · Cited by 74 · see citing works
“These findings were confirmed in additional AD mouse models [96, 97].”
ResultTwo-Photon Microscopy for Chemical Neuroscience
Ellis‐Davies, G. C. R. (2011) · ACS Chemical Neuroscience · doi:10.1021/cn100111a · Cited by 82 · see citing works
IVIg protects the 3xTg-AD mouse model of Alzheimer’s disease from memory deficit and Aβ pathology
St‐Amour, I., Paré, I., Tremblay, C., Coulombe, K., Bazin, R., & Calon, F. (2014) · Journal of Neuroinflammation · doi:10.1186/1742-2094-11-54 · Cited by 81 · see citing works
“The impact of CX3CR1 on neurodegeneration is still debated, but previously published data demonstrate a reduction of amyloid deposits and neuronal loss, and increased in vitro phagocytosis in knockout animals for CX3CR1 [35-37].”
Background
- Authors
- Liu, Z., Condello, C., Schain, A., Harb, R., & Grutzendler, J.
- Affiliations
- Northwestern University (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2010-12-15
- Volume
- 30
- Issue
- 50
- Pages
- 17091-17101
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3077120
- OpenAlex
- W2086776463
- Cited by
- 276
- References
- 42
- Citations by year
- 2026: 8 · 2025: 12 · 2024: 11 · 2023: 18 · 2022: 13 · 2021: 23 · 2020: 11 · 2019: 23 · 2018: 26 · 2017: 11 · 2016: 18 · 2015: 25 · 2014: 24 · 2013: 19 · 2012: 15
- FWCI
- 7.67
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- CX3CR1, microglia, amyloid-beta, Alzheimer's disease, phagocytosis, amyloid plaques, microglial activation, microglial proliferation
- MeSH terms
- CX3C Chemokine Receptor 1, Animals, Brain, Neurons
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.
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