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

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.

IVIg protects the 3xTg-AD mouse model of Alzheimer’s disease from memory deficit and Aβ pathology

“…However, genetic knockouts of CX3CR1 hardly mimic the actual trends in CX3CR1 expression in physiological conditions and during the progression of the disease. In the brain, the fractalkine pathway mediates the communication between neurons, which produce fractalkine, and microglia, which express CX3CR1, as binding of the two inhibits microglial activation [67]. In the present study, IVIg administration had no effect on brain expression levels of CX3CR1 or fractalkine, as detected by Western blot analysis.…”

Recombinant human interleukin-1 receptor antagonist promotes M1 microglia biased cytokines and chemokines following human traumatic brain injury

“…Second, there is in vitro evidence that fractalkine, a chemokine loads to a large degree on PC2, in addition to its well defined role as a monocyte chemoattractant, may also act directly on neurones to reduce apoptosis and cell loss. [31][32][33][34] Lastly, and perhaps most interestingly, is the interaction between the innate and adaptive immune systems and the possibility for classically activated macrophages to promote beneficial autoreactivity to neuronal antigens. 35,36 This is a feature of the neuro-inflammatory response to TBI that is, as yet, poorly explored.…”

Neurobiology of microglial action in CNS injuries: Receptor-mediated signaling mechanisms and functional roles

“…For example, increased CX3CL1-CX3CR1 signaling may be beneficial in early AD by restraining microglial activity and preventing the exacerbation of phosphorylated tau-mediated damage to neurons (Bhaskar et al, 2010;. However, sustained elevation of CX3CL1-CX3CR1 signaling may become detrimental by interfering with microglial phagocytosis in advanced stages when removal of extracellular Aβ deposits becomes necessary (Desforges et al, 2012;Lee et al, 2010). All of these complex issues need to be taken into full consideration when developing therapeutic interventions targeting CX3CR1.…”