Ccr2 deletion dissociates cavity size and tau pathology after mild traumatic brain injury

Stefka Gyoneva, Daniel Kim, Atsuko Katsumoto, O. Nicole Kokiko-Cochran, Bruce Lamb, Richard M. Ransohoff

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Background: Millions of people experience traumatic brain injury (TBI) as a result of falls, car accidents, sports injury, and blast. TBI has been associated with the development of neurodegenerative conditions such as Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE). In the initial hours and days, the pathology of TBI comprises neuronal injury, breakdown of the blood-brain barrier, and inflammation. At the cellular level, the inflammatory reaction consists of responses by brain-resident microglia, astrocytes, and vascular elements as well as infiltration of peripheral cells. After TBI, signaling by chemokine (C-C motif) ligand 2 (CCL2) to the chemokine (C-C motif) receptor 2 (CCR2) is a key regulator of brain infiltration by monocytes. Methods: We utilized mice with one or both copies of Ccr2 disrupted by red fluorescent protein (RFP, Ccr2 RFP/+ and Ccr2 RFP/RFP ). We subjected these mice to the mild lateral fluid percussion model of TBI and examined several pathological outcomes 3days later in order to determine the effects of altered monocyte entry into the brain. Results: Ccr2 deletion reduced monocyte infiltration, diminished lesion cavity volume, and lessened axonal damage after mild TBI, but the microglial reaction to the lesion was not affected. We further examined phosphorylation of the microtubule-associated protein tau, which aggregates in brains of people with TBI, AD, and CTE. Surprisingly, Ccr2 deletion was associated with increased tau mislocalization to the cell body in the cortex and hippocampus by tissue staining and increased levels of phosphorylated tau in the hippocampus by Western blot. Conclusions: Disruption of CCR2 enhanced tau pathology and reduced cavity volume in the context of TBI. The data reveal a complex role for CCR2+ monocytes in TBI, as monitored by cavity volume, axonal damage, and tau phosphorylation.

Original languageEnglish (US)
Article number228
JournalJournal of Neuroinflammation
Volume12
Issue number1
DOIs
StatePublished - Dec 3 2015
Externally publishedYes

Fingerprint

Brain Concussion
Pathology
Monocytes
Brain
Hippocampus
Alzheimer Disease
CCR Receptors
Phosphorylation
Percussion
Athletic Injuries
Microtubule-Associated Proteins
Traumatic Brain Injury
Chemokine CCL2
Microglia
Encephalitis
Blood-Brain Barrier
Astrocytes
Accidents
Blood Vessels
Western Blotting

Keywords

  • CCR2
  • MAPT
  • Monocyte
  • Tau
  • Traumatic brain injury

ASJC Scopus subject areas

  • Neuroscience(all)
  • Cellular and Molecular Neuroscience
  • Neurology
  • Immunology

Cite this

Ccr2 deletion dissociates cavity size and tau pathology after mild traumatic brain injury. / Gyoneva, Stefka; Kim, Daniel; Katsumoto, Atsuko; Kokiko-Cochran, O. Nicole; Lamb, Bruce; Ransohoff, Richard M.

In: Journal of Neuroinflammation, Vol. 12, No. 1, 228, 03.12.2015.

Research output: Contribution to journalArticle

Gyoneva, Stefka ; Kim, Daniel ; Katsumoto, Atsuko ; Kokiko-Cochran, O. Nicole ; Lamb, Bruce ; Ransohoff, Richard M. / Ccr2 deletion dissociates cavity size and tau pathology after mild traumatic brain injury. In: Journal of Neuroinflammation. 2015 ; Vol. 12, No. 1.
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abstract = "Background: Millions of people experience traumatic brain injury (TBI) as a result of falls, car accidents, sports injury, and blast. TBI has been associated with the development of neurodegenerative conditions such as Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE). In the initial hours and days, the pathology of TBI comprises neuronal injury, breakdown of the blood-brain barrier, and inflammation. At the cellular level, the inflammatory reaction consists of responses by brain-resident microglia, astrocytes, and vascular elements as well as infiltration of peripheral cells. After TBI, signaling by chemokine (C-C motif) ligand 2 (CCL2) to the chemokine (C-C motif) receptor 2 (CCR2) is a key regulator of brain infiltration by monocytes. Methods: We utilized mice with one or both copies of Ccr2 disrupted by red fluorescent protein (RFP, Ccr2 RFP/+ and Ccr2 RFP/RFP ). We subjected these mice to the mild lateral fluid percussion model of TBI and examined several pathological outcomes 3days later in order to determine the effects of altered monocyte entry into the brain. Results: Ccr2 deletion reduced monocyte infiltration, diminished lesion cavity volume, and lessened axonal damage after mild TBI, but the microglial reaction to the lesion was not affected. We further examined phosphorylation of the microtubule-associated protein tau, which aggregates in brains of people with TBI, AD, and CTE. Surprisingly, Ccr2 deletion was associated with increased tau mislocalization to the cell body in the cortex and hippocampus by tissue staining and increased levels of phosphorylated tau in the hippocampus by Western blot. Conclusions: Disruption of CCR2 enhanced tau pathology and reduced cavity volume in the context of TBI. The data reveal a complex role for CCR2+ monocytes in TBI, as monitored by cavity volume, axonal damage, and tau phosphorylation.",
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AU - Gyoneva, Stefka

AU - Kim, Daniel

AU - Katsumoto, Atsuko

AU - Kokiko-Cochran, O. Nicole

AU - Lamb, Bruce

AU - Ransohoff, Richard M.

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AB - Background: Millions of people experience traumatic brain injury (TBI) as a result of falls, car accidents, sports injury, and blast. TBI has been associated with the development of neurodegenerative conditions such as Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE). In the initial hours and days, the pathology of TBI comprises neuronal injury, breakdown of the blood-brain barrier, and inflammation. At the cellular level, the inflammatory reaction consists of responses by brain-resident microglia, astrocytes, and vascular elements as well as infiltration of peripheral cells. After TBI, signaling by chemokine (C-C motif) ligand 2 (CCL2) to the chemokine (C-C motif) receptor 2 (CCR2) is a key regulator of brain infiltration by monocytes. Methods: We utilized mice with one or both copies of Ccr2 disrupted by red fluorescent protein (RFP, Ccr2 RFP/+ and Ccr2 RFP/RFP ). We subjected these mice to the mild lateral fluid percussion model of TBI and examined several pathological outcomes 3days later in order to determine the effects of altered monocyte entry into the brain. Results: Ccr2 deletion reduced monocyte infiltration, diminished lesion cavity volume, and lessened axonal damage after mild TBI, but the microglial reaction to the lesion was not affected. We further examined phosphorylation of the microtubule-associated protein tau, which aggregates in brains of people with TBI, AD, and CTE. Surprisingly, Ccr2 deletion was associated with increased tau mislocalization to the cell body in the cortex and hippocampus by tissue staining and increased levels of phosphorylated tau in the hippocampus by Western blot. Conclusions: Disruption of CCR2 enhanced tau pathology and reduced cavity volume in the context of TBI. The data reveal a complex role for CCR2+ monocytes in TBI, as monitored by cavity volume, axonal damage, and tau phosphorylation.

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