Neuropathological, glial and behavioural changes following a TBI in a mouse model of amyloidosis

In Australia, it is estimated that 487,500 people live with dementia, with projections that this number will double by 2058. The most common neurodegenerative disease leading to dementia is Alzheimer's disease (AD). Accumulating epidemiological and pathological evidence implicates traumatic brain injury (TBI) as a risk factor for AD development, with amyloid-˜í‚⧠(A˜í‚â§) plaques observed in approximately 30% of severe human TBI cases. However, the effects of a mild/moderate TBI on A˜í‚⧠plaque deposition and disease trajectory are less clear. Whilst not everyone with a TBI develops dementia, more research is needed to understand why. One proposed link between TBI and AD is chronic glial involvement, particularly microglia and astrocytes. However, glia are dynamic cells, and their involvement is reported to change with age and differ between sex. In the normal aging process, glial function is altered and becomes 'primed', making glia more vulnerable to subsequent immune challenges. Priming is characterised by dystrophic glial morphology, altered phagocytosis and increased expression of inflammatory markers. Furthermore, priming is biologically sex-dependent, with mouse models demonstrating greater 'primed' profiles in aged female rodents. Therefore, age-at-injury and sex are essential considerations for the glial response to TBI. This thesis investigated the effects of a single diffuse TBI in APPswe/PS1dE9 (APP/PS1) mice, a model of the A˜í‚⧠pathology that characterises AD. APP/PS1 mice received a TBI at the onset (3 months of age) or mid-progression of A˜í‚⧠plaque deposition (9 months of age). This study incorporated two-time points: acute (7 days post-injury) and chronic (12 months of age, either 9 months or 3 months post-injury). Mice underwent motor and cognitive behavioural analysis and subsequent brain collection for immunohistochemistry and flow cytometry to determine glial and neuropathological changes. Immunohistochemical markers, including an A˜í‚⧠marker (MOAB2), a microglial marker (Iba1), a microglia phagocytosis marker (CD68) and a commonly associated astrocyte activation marker (GFAP), demonstrated distinct patterns of immunoreactivity which varied by biological sex, age, brain region and time since injury. Furthermore, flow cytometry was used to analyse microglia phagocytic capacity, demonstrating microglia to be sex- and age-dependent. These data suggest the circumstance of TBI results in specific glial responses that may determine TBI outcome. A˜í‚⧠pathology is associated with both TBI and AD. This thesis found that A˜í‚⧠pathology and behavioural changes accompanied the acute and chronic glial changes. A TBI at 9 months old acutely (7 days post-injury) decreased A˜í‚⧠plaque deposition in male transgenic (TG) mice compared to age-matched na‚àövòve mice. Acute motor deficits were also observed following an injury at 9 months in male mice, analysed through the hanging wire and beam walk test. At 12 months of age, injured male and female TG mice saw a reduction in A˜í‚⧠plaque deposition compared to age-matched TG na‚àövòve mice. Motor deficits accompanied these pathological and glial changes in male and female mice, and memory deficits were also observed in 9 month injured female mice assessed through the novel object recognition test. This thesis found that the glial link is more than just their presence and response, but the circumstance of the TBI, which resulted in specific glial responses. Furthermore, this thesis highlights the complexity of microglia and astrocytes and that their response to TBI was not only sex- and age-dependent but different between brain regions. Therefore, the glial response to TBI could explain the heterogeneity of TBI outcomes. Moreover, a TBI chronically alters glial function, which may exacerbate and accelerate the AD process.