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Updated: Jun 8, 2026
Cell-based Assay to Study Antibody-mediated Tau Clearance by Microglia
Published on: November 9, 2018
Regulation of tau pathology by the microglial fractalkine receptor
Kiran Bhaskar1, Megan Konerth, Olga N Kokiko-Cochran
1Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Abstract:
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 nontransgenic 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 (IL-1) 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 IL-1/p38 MAPK may serve as novel therapeutic targets for human tauopathies.
Insights
Microglial neuroinflammation drives tau protein (MAPT) phosphorylation and aggregation in tauopathies. Targeting CX3CR1 and IL-1/p38 MAPK pathways may offer new therapeutic strategies for these neurodegenerative diseases.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Tauopathies are characterized by aggregated hyperphosphorylated microtubule-associated protein tau (MAPT).
- Microglial neuroinflammation is increasingly recognized as a contributor to neurodegenerative processes.
- The role of microglial pathways in initiating tau pathology remains incompletely understood.
Purpose of the Study:
- To investigate the role of microglial activation and specific signaling pathways in promoting MAPT phosphorylation and aggregation.
- To identify potential therapeutic targets for tauopathies based on microglial-neuronal interactions.
Main Methods:
- Utilized lipopolysaccharide-induced microglial activation in wild-type and CX3CR1-deficient mice.
- Employed humanized MAPT transgenic mice lacking CX3CR1.
- Conducted in vitro experiments with primary neuronal cultures and activated microglia.
- Assessed MAPT phosphorylation, aggregation, p38 MAPK activation, and behavioral outcomes.
Main Results:
- Microglial activation significantly enhanced endogenous and transgenic MAPT phosphorylation and aggregation.
- Lack of CX3CR1 exacerbated MAPT pathology and behavioral deficits, correlating with increased p38 MAPK.
- In vitro studies confirmed that activated microglia increase neuronal MAPT hyperphosphorylation via IL-1 and p38 MAPK signaling.
- Interleukin-1 receptor antagonist and p38 MAPK inhibitors mitigated microglial-induced tau pathology.
Conclusions:
- Microglial neuroinflammation, particularly involving CX3CR1, IL-1, and p38 MAPK, is a key driver of MAPT phosphorylation and aggregation.
- These pathways represent promising therapeutic targets for mitigating tau pathology in tauopathies.
