In Parkinson's disease, α-synuclein is known to activate microglia and this activation has been proposed as one of the mechanisms of neurodegeneration. There are several signals produced by neurons that have an anti-inflammatory action on microglia, including CX3CL1 (fractalkine). We have shown that a soluble form of CX3CL1 is required to reduce neuron loss in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice and that fractalkine agonism can reduce neuron loss in a 6-hydroxydopamine lesion model. Here, we show that fractalkine can reduce α-synuclein-mediated neurodegeneration in rats. Rats that received fractalkine showed abrogated loss of tyrosine hydroxylase and Neu-N staining. This was replicated in animals where we expressed fractalkine from astrocytes with the glial fibrillary acid protein (GFAP) promoter. Interestingly, we did not observe a reduction in MHCII expression suggesting that soluble fractalkine is likely altering the microglial state to a more neuroprotective one rather than reducing antigen presentation.

Alzheimer’s disease (AD) is a progressive, neurodegenerative disorder, and the most common form of dementia. As the understanding of AD has progressed, it is now believed that AD is an amyloid-initiated tauopathy with neuroinflammation serving as the link between amyloid deposition, tau pathology, and neurodegeneration. As microglia are the main immune effectors in the central nervous system, they have been the focus of attention in studies investigating the neuroinflammatory component of AD. Therefore, recent work has focused on immunomodulators, which can alter microglial activation without suppressing activity, as potential therapeutics for AD. Fractalkine (CX3CL1; FKN), a unique chemokine with a one-to-one relationship with its receptor, signals through its cognate receptor (CX3CR1) to reduce expression of pro-inflammatory genes in activated microglia. Disrupting FKN signaling has opposing effects on the two hallmark pathologies of AD, but over-expressing a soluble FKN has been shown to reduce tau pathology while not altering amyloid pathology. Recently, differential signaling has been reported when comparing two cleavage variants of soluble FKN. These differential effects may explain recent studies reporting seemingly conflicting results regarding the effect of FKN over expression on AD pathologies.

Accumulating evidence increasingly implicates regulation of neuroinflammation as a potential therapeutic target in Alzheimer’s disease and other neurodegenerative disorders . Fractalkine (FKN) is a unique chemokine that is expressed and secreted by neurons and reduces expression of pro-inflammatory genes. To further demonstrate the utility of agents that increase FKN signaling throughout the central nervous system as possible therapies for AD, we assessed the impact of soluble FKN (sFKN) over expression on cognition in tau depositing rTg450 mice after the onset of cognitive deficits. Using adeno-associated virus serotype 4, we infected cells lining the ventricular system with soluble FKN to increase FKN signaling over a larger fraction of the brain than achieved with intraparenchymal injections. We found that soluble FKN over expression by cells lining the ventricles significantly improved cognitive performance on the novel mouse recognition and radial arm water maze tasks. These benefits were achieved without detectable reductions in tau hyperphosphorylation, hippocampal atrophy, or microglial CD45 expression. Utilizing qPCR, we report a significant increase in Vegfa expression, indicating an increase in trophic support and possible neovascularization in AAV-sFKN-injected mice. To our knowledge, this is the first demonstration that FKN over expression can rescue cognitive function in a tau depositing mouse line. Graphical Abstract Regulating neuroinflammation is an attractive therapeutic target for Alzheimer’s disease. Microglial activation can not only drive pathology but also accelerate cognitive decline. The chemokine fractalkine regulates the microglial phenotype, increasing trophic support of neurons, and significantly improving cognitive functioning in the rTg4510 mouse model of tauopathy.