Neuroinflammatory and protein responses to TBI

Morgan, Hannah Louise (2023) Neuroinflammatory and protein responses to TBI. PhD thesis, University of Glasgow.

Abstract

Background: Traumatic brain injury (TBI) is a leading cause of death and disability world-wide, affecting approximately 69 million individuals each year. It is also recognised as one of the major, modifiable risk factors in the development of neurodegenerative disease in later life, with exposure to moderate to severe single TBI and repetitive, mild TBI both recognised as contributing factors in the development of dementia. However, the neuropathological mechanisms contributing to late neurodegeneration remain uncertain. The complex polypathology emerging from the initial biomechanical injury mirror other neurodegenerative disease and include abnormal aggregation of proteins such as tau and Aβ and neuroinflammation, which will be explored in this thesis.
Methodology: Utilising material from the Glasgow TBI archive, in cohorts of patients aged ≤60 exposed to acute and long-term survival following moderate to severe, single TBI and appropriately age-matched controls, the role of the cellular adaptive immune response to injury was assessed through immunocytochemistry for T- and B-lymphocyte populations. These cohorts as well as tissue from patients exposed to repetitive mild TBI (rTBI) and appropriately matched controls were studied to characterise the differential astroglial response to injury across injury subgroups through measurement of GFAP, AQP4 and NQO1 immunoreactivity. A cohort of patients aged ≥60 years who survived acutely following moderate to severe, single TBI compared to age-matched, uninjured controls with no history of neurodegenerative disease, were examined to evaluate the effect of age and TBI using modifications of clinically recognised, standardised, semi-quantitative scoring systems of tau and Aβ immunoreactivity. Lastly, a protocol for the assessment of our archival, FFPE tissue was devised to allow comparison of proteomes of cohorts of patients exposed to mild rTBI, AD patients and appropriately matched controls, using liquid-chromatography mass-spectrometry.
Results: There is no histological evidence of a significant cellular response from the adaptive immune system following exposure to moderate to severe, single TBI in patients surviving acutely or long-term after injury, with no increase in T- or B-lymphocytes. There was, unexpectedly, a decrease in T-lymphocytes in long-term survivors of TBI. Contrastingly, there was an increase in reactive astrogliosis following exposure to TBI; demonstrated by an increase in AQP4-immunoractive astrocytes in acutely surviving patients and increase in GFAP expression in long-term surviving patients and an increase in NQO1 expression in rTBI patients compared to age-matched uninjured controls. There was also an increase in both AQP4 and GFAP expression in elderly uninjured controls compared to younger uninjured controls. Examining the expression of Aβ and tau in elderly patients exposed to single, moderate to severe TBI showed an increase in neuritic Aβ plaque and in the regional distribution of all plaque compared to uninjured, elderly controls, but no increase in expression or distribution of NFTs. Finally, a protocol for processing archival FFPE resulted in identification of 267 proteins from across rTBI, AD and uninjured, non-NND controls with significantly differential expression in 84 of them.
Conclusions: Together, these findings increase understanding of the neuropathological changes occurring following moderate to severe, single TBI and repetitive TBI. These data demonstrate that there is an astrogliotic but not adaptive cellular response after moderate to severe single TBI whilst also showing that age is correlated with an increase in reactive astrogliosis for several markers. Age was also examined in the examination of proteinopathic changes following acute survival after moderate to severe injury and changes suggest that TBI may occur as a result of increased amyloid pathology as neuritic plaque was observed > 2 weeks after injury. Lastly, that archival FFPE samples were successfully processed to allow identification of proteins from across a range of cohorts, revealing differences in protein expression that underpin the neuropathological changes which contribute to the long-term, post-TBI neurodegenerative process.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
• Supervisor's Name: Stewart, Prof. William
• Date of Award: 2023
• Depositing User: Theses Team
• Unique ID: glathesis:2023-83720
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 06 Jul 2023 11:47
• Last Modified: 06 Jul 2023 13:07
• Thesis DOI: 10.5525/gla.thesis.83720
• URI: https://theses.gla.ac.uk/id/eprint/83720