Loss of tau rescues inflammation-mediated neurodegeneration
Open accessAbstract
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.
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IL-1β is not sufficient to cause neurotoxicity or neurodegeneration in the absence of tau.
“However, it should be noted that IL-1β is not sufficient to cause neurotoxicity or neurodegeneration in the absence of tau [136, 138].”
From Glial contributions to neurodegeneration in tauopathies (2017) · cites this paper as [138]
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- Authors
- Maphis, N., Xu, G., Kokiko-Cochran, O. N., Cardona, A. E., Ransohoff, R. M., Lamb, B. T., & Bhaskar, K.
- Affiliations
- University of New Mexico (US)
- Cleveland Clinic (US)
- The University of Texas at San Antonio (US)
- Biogen (United States) (US)
- Corresponding author
- Bhaskar, Kiran
- Venue
- Frontiers in Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2015-06-03
- Volume
- 9
- Pages
- 196-196
- ISSN
- 1662-453X (ISSN-L)
- PMC
- PMC4452825
- OpenAlex
- W1548370718
- Cited by
- 91
- References
- 66
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 5 · 2023: 3 · 2022: 6 · 2021: 14 · 2020: 7 · 2019: 9 · 2018: 14 · 2017: 9 · 2016: 11 · 2015: 3
- FWCI
- 6.58
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Frontiers in Neuroscience (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- U.S. Department of Defense
- Alzheimer's Association (NIRG-11-204995)
- American Health Assistance Foundation
- CurePSP
- National Institutes of Health (UL1TR001449, UL1TR000439)
- School of Medicine, University of New Mexico
- National Institute on Aging (R01AG023012)
- National Institute of General Medical Sciences (SC1GM095426)
- National Institute of Neurological Disorders and Stroke (RF1NS083704, R21NS077089, NS074804, R01NS083704, R01NS074804)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- tau protein, neuroinflammation, neurodegeneration, microglia, CX3CR1, lipopolysaccharide, tauopathy, Alzheimer's disease, neuroprotection, neuronal apoptosis, microglial activation, neurobehavioral deficits
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