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Tau phosphorylation induced by severe closed head traumatic brain injury is linked to the cellular prion protein.

Abstract Studies in vivo and in vitro have suggested that the mechanism underlying Alzheimer's disease (AD) neuropathogenesis is initiated by an interaction between the cellular prion protein (PrP(C)) and amyloid-β oligomers (Aβo). This PrP(C)-Aβo complex activates Fyn kinase which, in turn, hyperphosphorylates tau (P-Tau) resulting in synaptic dysfunction, neuronal loss and cognitive deficits. AD transgenic mice lacking PrP(C) accumulate Aβ, but show normal survival and no loss of spatial learning and memory suggesting that PrP(C) functions downstream of Aβo production but upstream of intracellular toxicity within neurons. Since AD and traumatic brain injury (TBI)-linked chronic traumatic encephalopathy are tauopathies, we examined whether similar mechanistic pathways are responsible for both AD and TBI pathophysiologies. Using transgenic mice expressing different levels of PrP(C), our studies investigated the influence and necessity of PrP(C) on biomarker (total-tau [T-Tau], P-Tau, GFAP) levels in brain and blood as measured biochemically following severe TBI in the form of severe closed head injury (sCHI). We found that following sCHI, increasing levels of T-Tau and P-Tau in the brain were associated with the PrP(C) expression levels. A similar relationship between PrP(C) expression and P-Tau levels following sCHI were found in blood in the absence of significant T-Tau changes. This effect was not seen with GFAP which increased within 24 h following sCHI and progressively decreased by the 7 day time point regardless of the PrP(C) expression levels. Changes in the levels of all biomarkers were independent of gender. We further enhanced and expanded the quantitation of brain biomarkers with correlative studies using immunohisochemistry. We also demonstrate that a TBI-induced calpain hyperactivation is not required for the generation of P-Tau. A relationship was demonstrated between the presence/absence of PrP(C), the levels of P-Tau and cognitive dysfunction. Our studies suggest that PrP(C) is important in mediating TBI related pathology.
PMID
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Authors

Mayor MeshTerms
Keywords

Cellular prion protein

Cognition

GFAP

Immunohistochemistry

Tau phosphorylation

Total Tau

Traumatic brain injury

Journal Title acta neuropathologica communications
Publication Year Start




PMID- 28420443
OWN - NLM
STAT- In-Process
DA  - 20170419
LR  - 20170419
IS  - 2051-5960 (Electronic)
IS  - 2051-5960 (Linking)
VI  - 5
IP  - 1
DP  - 2017 Apr 18
TI  - Tau phosphorylation induced by severe closed head traumatic brain injury is
      linked to the cellular prion protein.
PG  - 30
LID - 10.1186/s40478-017-0435-7 [doi]
AB  - Studies in vivo and in vitro have suggested that the mechanism underlying
      Alzheimer's disease (AD) neuropathogenesis is initiated by an interaction between
      the cellular prion protein (PrPC) and amyloid-beta oligomers (Abetao). This
      PrPC-Abetao complex activates Fyn kinase which, in turn, hyperphosphorylates tau 
      (P-Tau) resulting in synaptic dysfunction, neuronal loss and cognitive deficits. 
      AD transgenic mice lacking PrPC accumulate Abeta, but show normal survival and no
      loss of spatial learning and memory suggesting that PrPC functions downstream of 
      Abetao production but upstream of intracellular toxicity within neurons. Since AD
      and traumatic brain injury (TBI)-linked chronic traumatic encephalopathy are
      tauopathies, we examined whether similar mechanistic pathways are responsible for
      both AD and TBI pathophysiologies. Using transgenic mice expressing different
      levels of PrPC, our studies investigated the influence and necessity of PrPC on
      biomarker (total-tau [T-Tau], P-Tau, GFAP) levels in brain and blood as measured 
      biochemically following severe TBI in the form of severe closed head injury
      (sCHI). We found that following sCHI, increasing levels of T-Tau and P-Tau in the
      brain were associated with the PrPC expression levels. A similar relationship
      between PrPC expression and P-Tau levels following sCHI were found in blood in
      the absence of significant T-Tau changes. This effect was not seen with GFAP
      which increased within 24 h following sCHI and progressively decreased by the 7
      day time point regardless of the PrPC expression levels. Changes in the levels of
      all biomarkers were independent of gender. We further enhanced and expanded the
      quantitation of brain biomarkers with correlative studies using
      immunohisochemistry. We also demonstrate that a TBI-induced calpain
      hyperactivation is not required for the generation of P-Tau. A relationship was
      demonstrated between the presence/absence of PrPC, the levels of P-Tau and
      cognitive dysfunction. Our studies suggest that PrPC is important in mediating
      TBI related pathology.
FAU - Rubenstein, Richard
AU  - Rubenstein R
AD  - Laboratory of Neurodegenerative Diseases and CNS Biomarker Discovery, Departments
      of Neurology and Physiology/ Pharmacology, SUNY Downstate Medical Center, 450
      Clarkson Avenue, Box #1213, Brooklyn, 11203-2098, NY, USA.
      [email protected]
FAU - Chang, Binggong
AU  - Chang B
AD  - Laboratory of Neurodegenerative Diseases and CNS Biomarker Discovery, Departments
      of Neurology and Physiology/ Pharmacology, SUNY Downstate Medical Center, 450
      Clarkson Avenue, Box #1213, Brooklyn, 11203-2098, NY, USA.
FAU - Grinkina, Natalia
AU  - Grinkina N
AD  - Laboratory of Neurodegenerative Diseases and CNS Biomarker Discovery, Departments
      of Neurology and Physiology/ Pharmacology, SUNY Downstate Medical Center, 450
      Clarkson Avenue, Box #1213, Brooklyn, 11203-2098, NY, USA.
FAU - Drummond, Eleanor
AU  - Drummond E
AD  - Center for Cognitive Neurology and Department of Neurology, New York University
      School of Medicine, Alexandria ERSP, 450 East 29th Street, New York, 10016, NY,
      USA.
FAU - Davies, Peter
AU  - Davies P
AD  - Litwin-Zucker Center for Research in Alzheimer's Disease, Feinstein Institute for
      Medical Research, Manhasset, 11030, NY, USA.
FAU - Ruditzky, Meir
AU  - Ruditzky M
AD  - Laboratory of Neurodegenerative Diseases and CNS Biomarker Discovery, Departments
      of Neurology and Physiology/ Pharmacology, SUNY Downstate Medical Center, 450
      Clarkson Avenue, Box #1213, Brooklyn, 11203-2098, NY, USA.
FAU - Sharma, Deep
AU  - Sharma D
AD  - Laboratory of Neurodegenerative Diseases and CNS Biomarker Discovery, Departments
      of Neurology and Physiology/ Pharmacology, SUNY Downstate Medical Center, 450
      Clarkson Avenue, Box #1213, Brooklyn, 11203-2098, NY, USA.
FAU - Wang, Kevin
AU  - Wang K
AD  - Program for Neurotrauma, Neuroproteomics and Biomarker Research, Departments of
      Psychiatry and Neuroscience, University of Florida, Gainesville, 32611, FL, USA.
FAU - Wisniewski, Thomas
AU  - Wisniewski T
AD  - Center for Cognitive Neurology and Departments of Neurology, Pathology and
      Psychiatry, New York University School of Medicine, Alexandria ERSP, 450 East
      29th Street, New York, 10016, NY, USA.
LA  - eng
PT  - Journal Article
DEP - 20170418
PL  - England
TA  - Acta Neuropathol Commun
JT  - Acta neuropathologica communications
JID - 101610673
OTO - NOTNLM
OT  - Cellular prion protein
OT  - Cognition
OT  - GFAP
OT  - Immunohistochemistry
OT  - Tau phosphorylation
OT  - Total Tau
OT  - Traumatic brain injury
EDAT- 2017/04/20 06:00
MHDA- 2017/04/20 06:00
CRDT- 2017/04/20 06:00
PHST- 2017/02/24 [received]
PHST- 2017/04/08 [accepted]
AID - 10.1186/s40478-017-0435-7 [doi]
AID - 10.1186/s40478-017-0435-7 [pii]
PST - epublish
SO  - Acta Neuropathol Commun. 2017 Apr 18;5(1):30. doi: 10.1186/s40478-017-0435-7.

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