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Chimera traumatic brain injury induces tauopathy in the RTG4510 mice
Author(s) -
Cheng Wai Hang,
Wilkinson Anna,
Cheung Honor,
Barron Carlos J,
Cripton Peter A,
Wellington Cheryl L
Publication year - 2020
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 - 10.1002/alz.047179
Subject(s) - traumatic brain injury , neuroinflammation , chimera (genetics) , tauopathy , chronic traumatic encephalopathy , medicine , neun , western blot , neuroscience , pathology , neurodegeneration , immunohistochemistry , poison control , concussion , biology , inflammation , injury prevention , biochemistry , disease , environmental health , psychiatry , gene
Background Traumatic brain injury (TBI) is a major cause of death and disabilities in developed countries. We have previously designed an animal TBI model called Closed Head Injury Model of Engineered Rotational Acceleration (CHIMERA). CHIMERA has the advantage of inducing precise non‐surgical head impacts without restricting head motion, thus inducing TBI relevant to a real‐world scenario. Using CHIMERA, we showed that repetitive mild TBI in a mouse model of amyloidosis led to neuropathological changes including neuroinflammation, fear memory deficits, and accumulation of soluble high molecular weight Aβ oligo/fibril. In the current study, we aim to study if CHIMERA TBI exacerbates tau pathologies, by inducing moderate/severe TBI (msTBI) to rTg4510 mice. Method 4‐mo male rTg4510 mice were used for this study. For the test group, a single msTBI TBI was induced at 4.0 J impact energy, with CHIMERA interface. For sham group, the animals received only anesthesia but no impact. 8 out of 13 animals survived the moderate/severe TBI procedure (38% mortality). The surviving animals were kept for 2‐mo, and the brain tissues were harvested for analysis using immunohistochemistry and Western blotting for multiple tau epitopes, neuroinflammation, and axonal injury. Blood samples were collected biweekly for biomarker analysis. Result TBI animals showed a significant increase duration of loss of righting. Histological analyses indicated significant microgliosis (Iba1) and axonal injury (Neurosilver) at white matter (optic tract), but no significant change in neuronal number (NeuN), astrocytes (GFAP), endothelial cells (CD31), or blood brain barrier integrity (IgG). There was a significant increase of one p‐tau epitope (PHF1), but not others (CP13, AT8, MC1, RZ3, or DA9). TBI also reduced the level of an inactive form of GSK‐3b (p‐GSK‐3b at S9). Interestingly, TBI animals showed a significant increase of P62 signals particularly at hippocampus, suggesting impaired autophagy. Conclusion Our current findings suggest a single msTBI is sufficient to induce p‐tau in rTg4510 mice, possibly through a reduction of inactive GSK‐3b. In addition, increased P62 signals may indicate impaired autophagy, which may lead to increased accumulation of neurodegenerative proteins at a later stage. More work has to be done to confirm long‐term tau and autophagy changes after TBI.