Cited by 91Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsNeurological Disease Mechanisms and Treatments

Loss of tau rescues inflammation-mediated neurodegeneration

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Maphis, Nicole, Xu, Guixiang, Kokiko-Cochran, Olga N., Cardona, Astrid E., Ransohoff, Richard M., Lamb, Bruce T., Bhaskar, Kiran·2015·Frontiers in Neuroscience

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.

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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
Published
2015-06-03
Volume
9
Pages
196-196
ISSN
1662-453X (ISSN-L)
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
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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