title: Evidence for accelerated tauopathy in the retina of transgenic P301S tau mice exposed to repetitive mild traumatic brain injury.
abstract: Chronic traumatic encephalopathy (CTE) is associated with repetitive mild traumatic brain injury (mTBI) in the context of contact and collision sports, but not all exposed individuals develop this condition. In addition, experiments in animal models in several laboratories have shown that non-transgenic mice do not develop tauopathy after exposure to repetitive mTBI schedules. It is thus reasonable to assume that genetic factors may play an etiological role in the development of CTE. More than 40 mutations in the tau gene are known to confer proneness to aggregation and are thought to cause neurodegenerative diseases including frontotemporal degeneration (FTD). Transgenic mice harboring these mutations can be used to ask the question whether repetitive mTBI can accelerate onset and course of tauopathy or worsen the outcomes of transgenic disease. In this study, we exposed mice harboring the tau P301S transgene associated with FTD to repetitive mTBI schedules by impact acceleration (IA) that we have previously characterized. We explored the progression of tauopathy in the retina and neocortex based on density of neuronal profiles loaded with tau pS422, a marker of advanced tau hyperphosphorylation. We found that the density of tau pS422 (+) retinal ganglion cells (RGCs) increased twenty fold with one mTBI hit, a little over fifty fold with four mTBI hits and sixty fold with 12 mTBI hits. The severity of mTBI burden (number of hits) was a significant factor in tauopathy outcome. On the other hand, we found no association between repetitive mTBI and density of pS422 (+) neuronal profiles in neocortex, a region that is not featured by significant TAI in our repetitive mTBI model. We observed similar, but less prominent, trends in tauopathy-prone transgenic mice harboring all 6 isoforms of wild-type human tau without mouse tau. Our findings indicate that repetitive mTBI accelerates tauopathy under diverse genetic conditions predisposing to tau aggregation and suggest a vulnerability-stress model in understanding some cases of acquired neurodegenerative disease after repetitive mTBI.
authors: Division of Neuropathology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: lxu9@jhmi.edu.
authors: Leyan
authors: L
authors: Xu
authors: Division of Neuropathology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: jryu4@jhmi.edu.
authors: Jiwon
authors: J
authors: Ryu
authors: Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: judy.v.nguyen@gmail.com.
authors: Judy V
authors: JV
authors: Nguyen
authors: Division of Neuropathology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: jarena2@jhmi.edu.
authors: John
authors: J
authors: Arena
authors: Division of Neuropathology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: lizrha@gmail.com.
authors: Elizabeth
authors: E
authors: Rha
authors: Division of Neuropathology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: pvranis1@jhu.edu.
authors: Pamela
authors: P
authors: Vranis
authors: Division of Neuropathology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: dhitt@sas.upenn.edu.
authors: Devon
authors: D
authors: Hitt
authors: Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD 21205, USA. Electronic address: marsh-armstrong@jhmi.edu.
authors: Nicholas
authors: N
authors: Marsh-Armstrong
authors: Division of Neuropathology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: koliat@jhmi.edu.
authors: Vassilis E
authors: VE
authors: Koliatsos
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001930:Brain Injuries / Q000150:complications*; D002452:Cell Count; D002540:Cerebral Cortex / Q000473:pathology; D004195:Disease Models, Animal; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D011392:Proline / Q000235:genetics; D011712:Pyramidal Tracts / Q000473:pathology; D012160:Retina / Q000378:metabolism / Q000473:pathology*; D012165:Retinal Ganglion Cells / Q000473:pathology; D012694:Serine / Q000235:genetics; D024801:Tauopathies / Q000150:complications / Q000235:genetics / Q000473:pathology*; D014795:Visual Pathways / Q000378:metabolism / Q000473:pathology; D051845:gamma-Synuclein / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics*
chemical_list: D051845:gamma-Synuclein; D016875:tau Proteins; D012694:Serine; D011392:Proline
keywords: CTE; Concussion; Diffuse axonal injury; Retina; Tau; Traumatic axonal injury