Regulation of Tau Pathology by the Microglial Fractalkine Receptor

By K. Bhaskar, Megan E. Konerth, O. Kokiko-Cochran, A. Cardona, R. Ransohoff, B. Lamb. Neuron, 2010

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SUMMARY Aggregates of the hyperphosphorylated microtubule associated protein tau (MAPT) are an invariant neuropathological feature of tauopathies. Here we show that microglial neuroinflammation promotes MAPT phosphorylation and aggregation. First, lipopolysaccharide-induced microglial activation promotes hyperphosphorylation of endogenous mouse MAPT in non-transgenic mice that is further enhanced in mice lacking the microglial-specific fractalkine receptor (CX3CR1) and is dependent upon functional toll-like receptor 4 and interleukin 1 (IL1) receptors. Second, humanized MAPT transgenic mice lacking CX3CR1 exhibited enhanced MAPT phosphorylation and aggregation as well as behavioral impairments that correlated with increased levels of active p38 MAPK. Third, in vitro experiments demonstrate that microglial activation elevates the level of active p38 MAPK and enhances MAPT hyperphosphorylation within neurons that can be blocked by administration of an interleukin 1 receptor antagonist and a specific p38 MAPK inhibitor. Taken together, our results suggest that CX3CR1 and IL1/p38 MAPK may serve as novel therapeutic targets for human tauopathies.

Subfields: Cellular and Molecular Neuroscience, Neurology, Physiology

View Paper: https://www.semanticscholar.org/paper/489eaee8b67fa5488cb4ddfa89e889fdb374ee19

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Citations in the corpus

Innate immunity in the central nervous system. (2012, positive): “By contrast, CX3CR1 deficiency worsens toxicity in t hyperphosphorylation models (67) and in models incorporating both pathologies, and complex effects are seen in models incorporating both pathologies (68).”
International Union of Basic and Clinical Pharmacology. LXXXIX. Update on the Extended Family of Chemokine Receptors and Introducing a New Nomenclature for Atypical Chemokine Receptors (2014, neutral): “Cx3cr1 deficiency was reported to promote microglial neurotoxicity in different neuropathologic murine models such as bacterial product-triggered inflammation, Parkinson’s disease, amyotrophic lateral sclerosis, and tau pathology (Cardona et al., 2006; Bhaskar et al., 2010).”
Inflammation as a central mechanism in Alzheimer's disease (2018, background): “[175] Bhaskar K, Konerth M, Kokiko-Cochran ON, Cardona A, Ransohoff RM, Lamb BT.”
Neuropathological alterations in Alzheimer disease. (2011, background): “In addition, recent experimental studies with in vitro and mouse models of AD have linked both astrocytes and microglia to neurodegeneration and have shown that activated microglia can lead to hyperphosphorylation and aggregation.(26,27) The idea of reactive glia as a hostile environment for Figure ”
Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023, background): “389 Furthermore, microglia could also phagocytize synapses that contain aggregated tau via synaptic tagging of C1q, leading to a decline in synapse density.”
Microglial cell origin and phenotypes in health and disease (2011, methodology): “When LPS was injected into the peritoneal cavities of mice, rapid and robust TLR4-induced transcription was observed in the brai”
Heterogeneity of CNS myeloid cells and their roles in neurodegeneration (2011, background): “Complementary findings emerged from examining the role of CX3CR1 in tau patholog”
Differential Roles of M1 and M2 Microglia in Neurodegenerative Diseases (2015, background): “Enhanced pro-inflammatory activation ofmicroglia by disruption of CX3CR1, an anti-inflammatory CX3CL1 receptor, accelerates tangle formation [120].”