Related Experiment Video
Updated: Apr 9, 2026
Lipidomics and Transcriptomics in Neurological Diseases
Published on: March 18, 2022
Loss of tau rescues inflammation-mediated neurodegeneration
Nicole Maphis1, Guixiang Xu2, Olga N Kokiko-Cochran2
1Department of Molecular Genetics and Microbiology, University of New Mexico Albuquerque, NM, USA.
Abstract:
Neuroinflammation is one of the neuropathological hallmarks of Alzheimer's disease (AD) and related tauopathies. Activated microglia spatially coexist with microtubule-associated protein tau (Mapt or tau)-burdened neurons in the brains of human AD and non-AD tauopathies. Numerous studies have suggested that neuroinflammation precedes tau pathology and that induction or blockage of neuroinflammation via lipopolysaccharide (LPS) or anti-inflammatory compounds (such as FK506) accelerate or block tau pathology, respectively in several animal models of tauopathy. We have previously demonstrated that microglia-mediated neuroinflammation via deficiency of the microglia-specific chemokine (fractalkine) receptor, CX3CR1, promotes tau pathology and neurodegeneration in a mouse model of LPS-induced systemic inflammation. Here, we demonstrate that tau mediates the neurotoxic effects of LPS in Cx3cr1 (-/-) mice. First, Mapt (+/+) neurons displayed elevated levels of Annexin V (A5) and TUNEL (markers of neurodegeneration) when co-cultured with LPS-treated Cx3cr1 (-/-)microglia, which is rescued in Mapt (-/-) neurons. Second, a neuronal population positive for phospho-S199 (AT8) tau in the dentate gyrus is also positive for activated or cleaved caspase (CC3) in the LPS-treated Cx3cr1 (-/-) mice. Third, genetic deficiency for tau in Cx3cr1 (-/-) mice resulted in reduced microglial activation, altered expression of inflammatory genes and a significant reduction in the number of neurons positive for CC3 compared to Cx3cr1 (-/-)mice. Finally, Cx3cr1 (-/-)mice exposed to LPS displayed a lack of inhibition in an open field exploratory behavioral test, which is rescued by tau deficiency. Taken together, our results suggest that pathological alterations in tau mediate inflammation-induced neurotoxicity and that deficiency of Mapt is neuroprotective. Thus, therapeutic approaches toward either reducing tau levels or blocking neuroinflammatory pathways may serve as a potential strategy in treating tauopathies.
Insights
Neuroinflammation drives tau pathology in Alzheimer's disease. Blocking tau or neuroinflammation may offer therapeutic benefits for tauopathies.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Neuroinflammation is a key feature of Alzheimer's disease (AD) and tauopathies.
- Activated microglia are found near tau-burdened neurons in human AD brains.
- Previous research suggests neuroinflammation precedes tau pathology.
Purpose of the Study:
- To investigate if tau mediates the neurotoxic effects of lipopolysaccharide (LPS)-induced inflammation in Cx3cr1-deficient mice.
- To determine if tau deficiency is neuroprotective in this inflammatory model.
Main Methods:
- Co-culture experiments with microglia and neurons from wild-type and tau-deficient mice.
- Analysis of neurodegeneration markers (Annexin V, TUNEL, cleaved caspase-3).
- Assessment of microglial activation and inflammatory gene expression.
- Behavioral testing (open field test) in mice with and without tau deficiency.
Main Results:
- LPS-treated Cx3cr1(-/-) microglia caused neurodegeneration in wild-type neurons, which was prevented in tau-deficient neurons.
- Tau pathology correlated with activated caspase-3 in LPS-treated Cx3cr1(-/-) mice.
- Tau deficiency reduced microglial activation, altered inflammatory gene expression, and decreased neurodegeneration.
- Tau deficiency rescued behavioral deficits in LPS-exposed Cx3cr1(-/-) mice.
Conclusions:
- Pathological tau mediates inflammation-induced neurotoxicity.
- Tau deficiency demonstrates neuroprotective effects in this model.
- Targeting tau or neuroinflammation offers potential therapeutic strategies for tauopathies.
