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Fractalkine Mediates Communication between Pathogenic Proteins and Microglia: Implications of Anti-Inflammatory Treatments in Different Stages of Neurodegenerative Diseases.

Desforges NM, Hebron ML, Algarzae NK, Lonskaya I, Moussa CE - Int J Alzheimers Dis (2012)

Bottom Line: Evidence in transgenic models suggests a beneficial effect of microglial activity on clearance of proteins like Aβ and a detrimental effect on Tau modification, but the role of CX3CL1 signaling in α-synucleinopathies is less clear.Here we review the nature of fractalkine-mediated neuronmicroglia interaction, which has significant implications for the efficacy of anti-inflammatory treatments during different stages of neurodegenerative pathology.Specifically, it is likely that anti-inflammatory treatment in early stages of disease during intraneuronal accumulation of proteins could be beneficial, while anti-inflammatory treatment in later stages when proteins are secreted to the extracellular space could exacerbate disease progression.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20057, USA.

ABSTRACT
The role of inflammation in neurodegenerative diseases has been widely demonstrated. Intraneuronal protein accumulation may regulate microglial activity via the fractalkine (CX3CL1) signaling pathway that provides a mechanism through which neurons communicate with microglia. CX3CL1 levels fluctuate in different stages of neurodegenerative diseases and in various animal models, warranting further investigation of the mechanisms underlying microglial response to pathogenic proteins, including Tau, β-amyloid (Aβ), and α-synuclein. The temporal relationship between microglial activity and localization of pathogenic proteins (intra- versus extracellular) likely determines whether neuroinflammation mitigates or exacerbates disease progression. Evidence in transgenic models suggests a beneficial effect of microglial activity on clearance of proteins like Aβ and a detrimental effect on Tau modification, but the role of CX3CL1 signaling in α-synucleinopathies is less clear. Here we review the nature of fractalkine-mediated neuronmicroglia interaction, which has significant implications for the efficacy of anti-inflammatory treatments during different stages of neurodegenerative pathology. Specifically, it is likely that anti-inflammatory treatment in early stages of disease during intraneuronal accumulation of proteins could be beneficial, while anti-inflammatory treatment in later stages when proteins are secreted to the extracellular space could exacerbate disease progression.

No MeSH data available.


Related in: MedlinePlus

Modulation of CX3CL1 in early versus late disease stages. The success of anti-inflammatory treatment in neurodegenerative diseases likely depends on the stage of disease progression. Treatment with NSAIDS early in disease pathology may alter the levels of various proinflammatory markers, including TNF-α, IL-6, IL-1β, and IL-1α, and anti-inflammatory markers, including TGF-β, IL-4, IL-10, and IL-34. The changes in the levels of these cytokines may lead to altered CX3CL1 signaling, which would either increase microglial activity (if CX3CL1 were reduced) or restrain microglia (if CX3CL1 levels were increased). In later stages of disease, secretion of pathogenic proteins like Aβ, α-synuclein, and p-Tau to the extracellular space increases microglial activation. Microglial activity promotes p-Tau, which destabilizes microtubules and leads to cell death. Treatment with NSAIDS in later stages of disease would likely be detrimental, as restraining microglia would weaken the immune response to remove extracellular protein aggregates.
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fig2: Modulation of CX3CL1 in early versus late disease stages. The success of anti-inflammatory treatment in neurodegenerative diseases likely depends on the stage of disease progression. Treatment with NSAIDS early in disease pathology may alter the levels of various proinflammatory markers, including TNF-α, IL-6, IL-1β, and IL-1α, and anti-inflammatory markers, including TGF-β, IL-4, IL-10, and IL-34. The changes in the levels of these cytokines may lead to altered CX3CL1 signaling, which would either increase microglial activity (if CX3CL1 were reduced) or restrain microglia (if CX3CL1 levels were increased). In later stages of disease, secretion of pathogenic proteins like Aβ, α-synuclein, and p-Tau to the extracellular space increases microglial activation. Microglial activity promotes p-Tau, which destabilizes microtubules and leads to cell death. Treatment with NSAIDS in later stages of disease would likely be detrimental, as restraining microglia would weaken the immune response to remove extracellular protein aggregates.

Mentions: Research on the suppression of microglial activity has been actively pursued with limited success [121] and strategies to manipulate the protective role of microglia—the detection and removal of apoptotic cells—have not been fully investigated [122–124]. These strategies warrant further research, as apoptotic cells that enter secondary necrosis [125] and trigger inflammation [126, 127] increase tissue damage. In this context, the role of CX3CL1 in mediating communication between preapoptotic neurons and microglia becomes greatly important. Such intervention would be relevant in early stages of disease progression, during which intracellular accumulation of pathogenic proteins anticipates apoptosis and the formation of extracellular protein aggregates. In later stages of disease pathology, decreased CX3CL1 signaling may activate microglia and induce p-Tau (Figure 2), which exacerbates disease progression by promoting apoptosis. Additionally, the use of NSAIDs to restrain microglial activity may exacerbate pathology due to lack of phagocytic clearance of secreted extracellular amyloids, including α-Synuclein, Aβ and p-Tau. In this context, targeting microglial activity in later disease stages may be detrimental and contributory to disease progression. However, targeting the CX3CL1 pathway in early disease stages could be beneficial, at least in delaying disease progression via restraint of microglial activity. Along this line of thought, NSAIDs administration could regulate key proinflammatory cytokines (Figure 2) that would modulate CX3CL1 signaling and microglial activity. It remains to be fully elucidated when and how alteration of proinflammatory markers may increase or decrease CX3CL1 signaling, which may either activate or suppress microglia. One possibility is increased CX3CL1 levels to restrain microglial activity and prevent the exacerbation of p-Tau damage. However, this intervention should be timed to avoid interference with microglial activity when patients progress into more advanced stages of disease, during which removal of extracellular deposits becomes necessary. Therefore, understanding the critical interplay between proinflammatory (TNF-α, IL-6, IL-1β, and IL-1α), anti-inflammatory cytokines (IL-10, TGF-β, IL-34, etc.), and fractalkine levels to modulate microglial activity is highly significant. Furthermore, whether the activation of microglia in the context of neurodegenerative disease is beneficial or detrimental may also depend upon the type of disease. Successful anti-inflammatory treatments of CNS diseases will likely be specific not only to the stage of disease pathology, but also to the type of disease. It has been found that many of the same cytokines are implicated in the pathology of AD, PD, and ALS despite distinct patterns of neuronal loss in each disease [9]. Previous literature presents contradictory evidence regarding the effects of targeting microglia in various CNS diseases. Glass et al. [128], for example, suggest that targeting microglia in PD and ALS is detrimental while other studies suggest that targeting microglia aids in Aβ clearance in AD. Further investigation of the role of the inflammatory response in each disease will determine the potential for anti-inflammatory treatments. Here we suggest a temporally-defined strategy of intervention in which early targeting of CX3CL1 signaling slows disease progression and prevents p-Tau formation.


Fractalkine Mediates Communication between Pathogenic Proteins and Microglia: Implications of Anti-Inflammatory Treatments in Different Stages of Neurodegenerative Diseases.

Desforges NM, Hebron ML, Algarzae NK, Lonskaya I, Moussa CE - Int J Alzheimers Dis (2012)

Modulation of CX3CL1 in early versus late disease stages. The success of anti-inflammatory treatment in neurodegenerative diseases likely depends on the stage of disease progression. Treatment with NSAIDS early in disease pathology may alter the levels of various proinflammatory markers, including TNF-α, IL-6, IL-1β, and IL-1α, and anti-inflammatory markers, including TGF-β, IL-4, IL-10, and IL-34. The changes in the levels of these cytokines may lead to altered CX3CL1 signaling, which would either increase microglial activity (if CX3CL1 were reduced) or restrain microglia (if CX3CL1 levels were increased). In later stages of disease, secretion of pathogenic proteins like Aβ, α-synuclein, and p-Tau to the extracellular space increases microglial activation. Microglial activity promotes p-Tau, which destabilizes microtubules and leads to cell death. Treatment with NSAIDS in later stages of disease would likely be detrimental, as restraining microglia would weaken the immune response to remove extracellular protein aggregates.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3420133&req=5

fig2: Modulation of CX3CL1 in early versus late disease stages. The success of anti-inflammatory treatment in neurodegenerative diseases likely depends on the stage of disease progression. Treatment with NSAIDS early in disease pathology may alter the levels of various proinflammatory markers, including TNF-α, IL-6, IL-1β, and IL-1α, and anti-inflammatory markers, including TGF-β, IL-4, IL-10, and IL-34. The changes in the levels of these cytokines may lead to altered CX3CL1 signaling, which would either increase microglial activity (if CX3CL1 were reduced) or restrain microglia (if CX3CL1 levels were increased). In later stages of disease, secretion of pathogenic proteins like Aβ, α-synuclein, and p-Tau to the extracellular space increases microglial activation. Microglial activity promotes p-Tau, which destabilizes microtubules and leads to cell death. Treatment with NSAIDS in later stages of disease would likely be detrimental, as restraining microglia would weaken the immune response to remove extracellular protein aggregates.
Mentions: Research on the suppression of microglial activity has been actively pursued with limited success [121] and strategies to manipulate the protective role of microglia—the detection and removal of apoptotic cells—have not been fully investigated [122–124]. These strategies warrant further research, as apoptotic cells that enter secondary necrosis [125] and trigger inflammation [126, 127] increase tissue damage. In this context, the role of CX3CL1 in mediating communication between preapoptotic neurons and microglia becomes greatly important. Such intervention would be relevant in early stages of disease progression, during which intracellular accumulation of pathogenic proteins anticipates apoptosis and the formation of extracellular protein aggregates. In later stages of disease pathology, decreased CX3CL1 signaling may activate microglia and induce p-Tau (Figure 2), which exacerbates disease progression by promoting apoptosis. Additionally, the use of NSAIDs to restrain microglial activity may exacerbate pathology due to lack of phagocytic clearance of secreted extracellular amyloids, including α-Synuclein, Aβ and p-Tau. In this context, targeting microglial activity in later disease stages may be detrimental and contributory to disease progression. However, targeting the CX3CL1 pathway in early disease stages could be beneficial, at least in delaying disease progression via restraint of microglial activity. Along this line of thought, NSAIDs administration could regulate key proinflammatory cytokines (Figure 2) that would modulate CX3CL1 signaling and microglial activity. It remains to be fully elucidated when and how alteration of proinflammatory markers may increase or decrease CX3CL1 signaling, which may either activate or suppress microglia. One possibility is increased CX3CL1 levels to restrain microglial activity and prevent the exacerbation of p-Tau damage. However, this intervention should be timed to avoid interference with microglial activity when patients progress into more advanced stages of disease, during which removal of extracellular deposits becomes necessary. Therefore, understanding the critical interplay between proinflammatory (TNF-α, IL-6, IL-1β, and IL-1α), anti-inflammatory cytokines (IL-10, TGF-β, IL-34, etc.), and fractalkine levels to modulate microglial activity is highly significant. Furthermore, whether the activation of microglia in the context of neurodegenerative disease is beneficial or detrimental may also depend upon the type of disease. Successful anti-inflammatory treatments of CNS diseases will likely be specific not only to the stage of disease pathology, but also to the type of disease. It has been found that many of the same cytokines are implicated in the pathology of AD, PD, and ALS despite distinct patterns of neuronal loss in each disease [9]. Previous literature presents contradictory evidence regarding the effects of targeting microglia in various CNS diseases. Glass et al. [128], for example, suggest that targeting microglia in PD and ALS is detrimental while other studies suggest that targeting microglia aids in Aβ clearance in AD. Further investigation of the role of the inflammatory response in each disease will determine the potential for anti-inflammatory treatments. Here we suggest a temporally-defined strategy of intervention in which early targeting of CX3CL1 signaling slows disease progression and prevents p-Tau formation.

Bottom Line: Evidence in transgenic models suggests a beneficial effect of microglial activity on clearance of proteins like Aβ and a detrimental effect on Tau modification, but the role of CX3CL1 signaling in α-synucleinopathies is less clear.Here we review the nature of fractalkine-mediated neuronmicroglia interaction, which has significant implications for the efficacy of anti-inflammatory treatments during different stages of neurodegenerative pathology.Specifically, it is likely that anti-inflammatory treatment in early stages of disease during intraneuronal accumulation of proteins could be beneficial, while anti-inflammatory treatment in later stages when proteins are secreted to the extracellular space could exacerbate disease progression.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20057, USA.

ABSTRACT
The role of inflammation in neurodegenerative diseases has been widely demonstrated. Intraneuronal protein accumulation may regulate microglial activity via the fractalkine (CX3CL1) signaling pathway that provides a mechanism through which neurons communicate with microglia. CX3CL1 levels fluctuate in different stages of neurodegenerative diseases and in various animal models, warranting further investigation of the mechanisms underlying microglial response to pathogenic proteins, including Tau, β-amyloid (Aβ), and α-synuclein. The temporal relationship between microglial activity and localization of pathogenic proteins (intra- versus extracellular) likely determines whether neuroinflammation mitigates or exacerbates disease progression. Evidence in transgenic models suggests a beneficial effect of microglial activity on clearance of proteins like Aβ and a detrimental effect on Tau modification, but the role of CX3CL1 signaling in α-synucleinopathies is less clear. Here we review the nature of fractalkine-mediated neuronmicroglia interaction, which has significant implications for the efficacy of anti-inflammatory treatments during different stages of neurodegenerative pathology. Specifically, it is likely that anti-inflammatory treatment in early stages of disease during intraneuronal accumulation of proteins could be beneficial, while anti-inflammatory treatment in later stages when proteins are secreted to the extracellular space could exacerbate disease progression.

No MeSH data available.


Related in: MedlinePlus