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O1‐06‐04: A DYNAMIC PERK‐TAU COMPLEX REGULATES TAU PHOSPHORYLATION, ER STRESS, AND TREATMENT OUTCOMES IN RTG4510 MICE
Author(s) -
Fontaine Sarah N.,
Nation Grant K.,
Koren Shon,
Weiss Blaine,
Cloyd Ryan,
Meier Shelby E.,
Chishti Emad,
Powell David K.,
Vandsburger Moriel,
Abisambra Joe F.
Publication year - 2018
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2018.06.2363
Subject(s) - tauopathy , phosphorylation , tau protein , immunoprecipitation , microbiology and biotechnology , kinase , chemistry , biology , neuroscience , medicine , cell culture , neurodegeneration , genetics , alzheimer's disease , disease
Background: Despite growing awareness of putative links between head injury and CTE, the substrates and mechanisms underpinning this association, and relationships to concussion and TBI, remain largely unknown and matters of significant controversy. Most notably, there is insufficient knowledge regarding changes in brain structure and function during the acute-subacute period after head injury that may represent the earliest antecedent pathologies of CTE. Methods: Here we combined human clinicopathological correlation analysis, animal and experimental modeling, and biomechanical and computational simulations to investigate these questions.Results:We examined postmortem brains from teenage athletes in the acute-subacute period after symptomatic closed-head impact injury and found astrocytosis, axonopathy, microvascular injury, perivascular neuroinflammation, and phosphorylated tau protein pathology. To investigate causalmechanisms, we developed a mouse model of closed-head impact injury that uses momentum transfer to induce traumatic head acceleration. Experimental impact injury was associated with axonopathy, bloodbrain barrier disruption, TGFb1/pSMAD2-associated astrocytosis, TREM2+ microgliosis, monocyte infiltration, and phosphorylated tauopathy in ipsilateral cerebral cortex. Phosphorylated tauopathy was detected in ipsilateral axons by 24 hours, bilateral axons and soma by 2 weeks, and distant cortex bilaterally at 5.5 months postinjury. Impact pathologies colocalized with serum albumin extravasation in the brain that was diagnostically detectable in living mice by dynamic contrast-enhanced magnetic resonance imaging. Transient neurobehavioral deficits at the time of injury did not correlate with blood-brain barrier disruption, microgliosis, neuroinflammation, phosphorylated tauopathy, or electrophysiological dysfunction postinjury. Computational modeling showed that impact injury generated point loading on the head and high-amplitude peak shear stress in the brain. Moreover, intracerebral shear stress peaked before onset of gross head motion. Conclusions:We conclude that fast-acting, highamplitude cortical shear stress triggers acute neurobehavioral deficits associated with concussion, whereas longer duration, lower amplitude shear stress associatedwith headmotion induces structural brain damage and neuropathological sequelae. These results suggest that closed-head impact injuries, independent of concussive signs, can induce traumatic brain injury as well as early pathologies and functional sequelae associated with chronic traumatic encephalopathy. These findings also shed light on the origins of concussion anddifferentiate this condition from traumatic brain injury and sequelae.