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Acta Neuropathologica

, Volume 131, Issue 1, pp 115–135 | Cite as

SNTF immunostaining reveals previously undetected axonal pathology in traumatic brain injury

  • Victoria E. Johnson
  • William Stewart
  • Maura T. Weber
  • D. Kacy Cullen
  • Robert Siman
  • Douglas H. Smith
Original Paper

Abstract

Diffuse axonal injury (DAI) is a common feature of severe traumatic brain injury (TBI) and may also be a predominant pathology in mild TBI or “concussion”. The rapid deformation of white matter at the instant of trauma can lead to mechanical failure and calcium-dependent proteolysis of the axonal cytoskeleton in association with axonal transport interruption. Recently, a proteolytic fragment of alpha-II spectrin, “SNTF”, was detected in serum acutely following mild TBI in patients and was prognostic for poor clinical outcome. However, direct evidence that this fragment is a marker of DAI has yet to be demonstrated in either humans following TBI or in models of mild TBI. Here, we used immunohistochemistry (IHC) to examine for SNTF in brain tissue following both severe and mild TBI. Human severe TBI cases (survival <7d; n = 18) were compared to age-matched controls (n = 16) from the Glasgow TBI archive. We also examined brains from an established model of mild TBI at 6, 48 and 72 h post-injury versus shams. IHC specific for SNTF was compared to that of amyloid precursor protein (APP), the current standard for DAI diagnosis, and other known markers of axonal pathology including non-phosphorylated neurofilament-H (SMI-32), neurofilament-68 (NF-68) and compacted neurofilament-medium (RMO-14) using double and triple immunofluorescent labeling. Supporting its use as a biomarker of DAI, SNTF immunoreactive axons were observed at all time points following both human severe TBI and in the model of mild TBI. Interestingly, SNTF revealed a subpopulation of degenerating axons, undetected by the gold-standard marker of transport interruption, APP. While there was greater axonal co-localization between SNTF and APP after severe TBI in humans, a subset of SNTF positive axons displayed no APP accumulation. Notably, some co-localization was observed between SNTF and the less abundant neurofilament subtype markers. Other SNTF positive axons, however, did not co-localize with any other markers. Similarly, RMO-14 and NF-68 positive axonal pathology existed independent of SNTF and APP. These data demonstrate that multiple pathological axonal phenotypes exist post-TBI and provide insight into a more comprehensive approach to the neuropathological assessment of DAI.

Keywords

Traumatic brain injury TBI Concussion Mild TBI Diffuse axonal injury Spectrin breakdown SNTF Axonal pathology Amyloid precursor protein Neurofilaments 

Notes

Acknowledgments

This work was supported by National Institutes of Health grants NS056202 (D.H. Smith and R. Siman), NS038104 (D.H. Smith), NS092389 (D.H. Smith), the US Department of Defense Grant PT110785 (D.H. Smith) and the NHS Research Scotland Career Research Fellowship (W. Stewart). We would like to thank Dr. John Wolf and Michael Grovola for their assistance with confocal imaging.

Compliance with ethical standards

Conflict of interest

Dr. Siman is listed as inventor on patent applications for SNTF as a blood biomarker for concussion. All other authors declare that they have no conflict of interest.

Ethical approvals

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of study, formal consent is not required.

Supplementary material

401_2015_1506_MOESM1_ESM.tif (24.1 mb)
Fig. S1 Controls for triple labeling studies. Injured tissue (human and swine) was subjected to labeling with antibodies for either APP (purple), SNTF (red) or NF-subtype (green) on serial sections. All sections received all secondary antibodies and were subjected to confocal imaging. Column (a-u) shows the merged image from all channels combined, (b-v) shows the red channel only (c-w) shows the green channel only and (d-x) shows the purple channel only. Rows (a-l) shows human TBI tissue stained for (a-d) APP only, (e-h) SNTF only and (i-l) RMO-14 only. Rows (m-x) shows swine mTBI tissue stained for (m-p) APP only, (q-t) SNTF only and (u-x) NF-L only. All scale bars 50µm (TIFF 24681 kb)
401_2015_1506_MOESM2_ESM.tif (24.1 mb)
Fig. S2 Serial sections of injured tissue were subjected to 3 independent antibodies specific for SNTF. Images acquired from the same region of injured tissue show specific staining of axons with an injured morphology using antibodies (a-c) 2233, (d-f) 2234 and (g-i) Ab37. Note an absence of immunoreactivity in the neuronal somata in the cortex (c, f, i). Scale bars (a, b, d, h) 50µm, (c, f, i) 100µm, (e, g) 25µm (TIFF 24681 kb)
401_2015_1506_MOESM3_ESM.tif (24.1 mb)
Fig. S3 Representative images showing SNTF (2233) immunoreactivity in the somata and dendrites in the cingulate cortex of (a-c) a 58 year old male who died 24 hours following severe TBI. A 41 year old control in (d) shows no SNTF immunoreactivity in somata or dendrites. All scale bars 100µm (TIFF 24683 kb)
401_2015_1506_MOESM4_ESM.tif (24.1 mb)
Fig. S4. All channels from triple immunofluorescent labeling in swine tissue shown in Figure 5. a-d shows triple labeling with SNTF (2233) (red), SMI-32 (green) and APP (purple) in a TBI case. e-p shows triple immunofluorescent labeling using SNTF (2233) (red), NF-68 (green) and APP (purple) at 6 hours (e-h) and 48 hours (i-l) post-mTBI, as well as a sham animal (m-p). q-x shows triple immunofluorescent labeling in swine with SNTF (2233) (red), RMO-14 (green) and APP (purple) at 48 hours post-mTBI (q-t) versus a sham animal (u-x). Scale bars (a-d, m-x) 100µm, (e-l) 50µm (TIFF 24699 kb)
401_2015_1506_MOESM5_ESM.tif (24.1 mb)
Fig. S5 All channels from triple immunofluorescent labeling in human tissue shown in Figure 8. (a-h) shows triple labeling with SNTF (2233) (red), SMI-32 (green) and APP (purple) in a TBI case (a-d) and a control (e-h). (i-p) Shows triple immunofluorescent labeling in humans with SNTF (2233) (red), NF-68 (green) and APP (purple) following TBI (i-l), and in a control (m-p). Scale bars (a-d,i-p) 100µm, (e-h) 50µm (TIFF 24698 kb)
401_2015_1506_MOESM6_ESM.tif (24.1 mb)
Fig. S6 All channels from triple immunofluorescent labeling in human tissue shown in Figure 8 with SNTF (2233) (red), RMO-14 (green) and APP (purple) in a TBI case (a-d) and a control (e-h). All scale bars 100µm (TIFF 24683 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Victoria E. Johnson
    • 1
  • William Stewart
    • 1
    • 2
    • 3
  • Maura T. Weber
    • 1
  • D. Kacy Cullen
    • 1
  • Robert Siman
    • 1
  • Douglas H. Smith
    • 1
  1. 1.Department of Neurosurgery, Penn Center for Brain Injury and Repair, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  2. 2.Department of NeuropathologyQueen Elizabeth Glasgow University HospitalGlasgowUK
  3. 3.University of GlasgowGlasgowUK

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