Loss of tau rescues inflammation-mediated neurodegeneration

Nicole Maphis, Guixiang Xu, Olga N. Kokiko-cochran, Astrid Cardona, Richard M. Ransohoff, Bruce Lamb, Kiran Bhaskar

Research output: Contribution to journalArticle

37 Citations (Scopus)

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 towards either reducing tau levels or blocking neuroinflammatory pathways may serve as a potential strategy in treating tauopathies.

Original languageEnglish (US)
Article number196
JournalFrontiers in Neuroscience
Volume9
Issue numberMAY
DOIs
StatePublished - 2015
Externally publishedYes

Fingerprint

Tauopathies
Lipopolysaccharides
Microglia
Inflammation
Neurons
Annexin A5
Pathology
Alzheimer Disease
Microtubule-Associated Proteins
Chemokine Receptors
Dentate Gyrus
In Situ Nick-End Labeling
Tacrolimus
Caspases
Anti-Inflammatory Agents
Animal Models
Gene Expression
Brain
Population

Keywords

  • Alzheimer's disease
  • Cx3cr1
  • CX3CR1 knockout and neurodegeneration
  • Fractalkine receptor
  • Microglia
  • Microtubule associated protein tau (MAPT)
  • Neuroinflammation
  • Tau knockout
  • Tau protein
  • Tauopathies

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Maphis, N., Xu, G., Kokiko-cochran, O. N., Cardona, A., Ransohoff, R. M., Lamb, B., & Bhaskar, K. (2015). Loss of tau rescues inflammation-mediated neurodegeneration. Frontiers in Neuroscience, 9(MAY), [196]. https://doi.org/10.3389/fnins.2015.00196

Loss of tau rescues inflammation-mediated neurodegeneration. / Maphis, Nicole; Xu, Guixiang; Kokiko-cochran, Olga N.; Cardona, Astrid; Ransohoff, Richard M.; Lamb, Bruce; Bhaskar, Kiran.

In: Frontiers in Neuroscience, Vol. 9, No. MAY, 196, 2015.

Research output: Contribution to journalArticle

Maphis, N, Xu, G, Kokiko-cochran, ON, Cardona, A, Ransohoff, RM, Lamb, B & Bhaskar, K 2015, 'Loss of tau rescues inflammation-mediated neurodegeneration', Frontiers in Neuroscience, vol. 9, no. MAY, 196. https://doi.org/10.3389/fnins.2015.00196
Maphis N, Xu G, Kokiko-cochran ON, Cardona A, Ransohoff RM, Lamb B et al. Loss of tau rescues inflammation-mediated neurodegeneration. Frontiers in Neuroscience. 2015;9(MAY). 196. https://doi.org/10.3389/fnins.2015.00196
Maphis, Nicole ; Xu, Guixiang ; Kokiko-cochran, Olga N. ; Cardona, Astrid ; Ransohoff, Richard M. ; Lamb, Bruce ; Bhaskar, Kiran. / Loss of tau rescues inflammation-mediated neurodegeneration. In: Frontiers in Neuroscience. 2015 ; Vol. 9, No. MAY.
@article{f4a4962e2944403b96449ed33c02132b,
title = "Loss of tau rescues inflammation-mediated neurodegeneration",
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 towards either reducing tau levels or blocking neuroinflammatory pathways may serve as a potential strategy in treating tauopathies.",
keywords = "Alzheimer's disease, Cx3cr1, CX3CR1 knockout and neurodegeneration, Fractalkine receptor, Microglia, Microtubule associated protein tau (MAPT), Neuroinflammation, Tau knockout, Tau protein, Tauopathies",
author = "Nicole Maphis and Guixiang Xu and Kokiko-cochran, {Olga N.} and Astrid Cardona and Ransohoff, {Richard M.} and Bruce Lamb and Kiran Bhaskar",
year = "2015",
doi = "10.3389/fnins.2015.00196",
language = "English (US)",
volume = "9",
journal = "Frontiers in Neuroscience",
issn = "1662-4548",
publisher = "Frontiers Research Foundation",
number = "MAY",

}

TY - JOUR

T1 - Loss of tau rescues inflammation-mediated neurodegeneration

AU - Maphis, Nicole

AU - Xu, Guixiang

AU - Kokiko-cochran, Olga N.

AU - Cardona, Astrid

AU - Ransohoff, Richard M.

AU - Lamb, Bruce

AU - Bhaskar, Kiran

PY - 2015

Y1 - 2015

N2 - 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 towards either reducing tau levels or blocking neuroinflammatory pathways may serve as a potential strategy in treating tauopathies.

AB - 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 towards either reducing tau levels or blocking neuroinflammatory pathways may serve as a potential strategy in treating tauopathies.

KW - Alzheimer's disease

KW - Cx3cr1

KW - CX3CR1 knockout and neurodegeneration

KW - Fractalkine receptor

KW - Microglia

KW - Microtubule associated protein tau (MAPT)

KW - Neuroinflammation

KW - Tau knockout

KW - Tau protein

KW - Tauopathies

UR - http://www.scopus.com/inward/record.url?scp=84930678292&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84930678292&partnerID=8YFLogxK

U2 - 10.3389/fnins.2015.00196

DO - 10.3389/fnins.2015.00196

M3 - Article

AN - SCOPUS:84930678292

VL - 9

JO - Frontiers in Neuroscience

JF - Frontiers in Neuroscience

SN - 1662-4548

IS - MAY

M1 - 196

ER -