CNS-Wide over Expression of Fractalkine Improves Cognitive Functioning in a Tauopathy Model

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...

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Bibliographic Details
Published in:Journal of neuroimmune pharmacology 2019-06, Vol.14 (2), p.312-325
Main Authors: Finneran, Dylan J., Morgan, Dave, Gordon, Marcia N., Nash, Kevin R.
Format: Article
Language:English
Subjects:
Biomedical and Life Sciences
Biomedicine
Cell Biology
Chemokines
Immunology
Neurosciences
Original
Original Article
Pharmacology/Toxicology
Virology
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Summary: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.
ISSN:1557-1890
1557-1904
DOI:10.1007/s11481-018-9822-5