The effect of traumatic brain injury in experimental models of Alzheimer’s disease

Traumatic brain injury (TBI) can cause persistent cognitive changes and ongoing neurodegeneration in the brain. Accumulating epidemiological and pathological evidence implicates TBI in the development of Alzheimer’s disease (AD). Furthermore, repetitive TBI is shown to cause the neurodegenerative condition chronic traumatic encephalopathy, which has many clinical and pathological similarities to AD. AD is characterized by three main pathological hallmarks: extracellular plaques composed of beta-amyloid (Aβ), dystrophic neurites and intracellular neurofibrillary tangles composed of tau. The amyloid cascade hypothesis posits that the accumulation of Aβ in the brain is a principal factor in AD pathogenesis, and genetic mutations causing enhanced Aβ formation result in early-onset AD. Aβ plaques have been demonstrated in approximately 30% of severe TBI cases, however the effects of mild/moderate non-fatal TBI on Aβ plaque deposition remains unclear. Furthermore, the underlying mechanisms and risk factors for Aβ plaque deposition after TBI are unknown. Thus, this thesis investigated the effects of a single TBI on the onset and progression of Aβ plaque deposition in the APPswe/PS1dE9 (APP/PS1) transgenic mouse model of AD. Two models of TBI were utilized in this thesis. The first model was a focal cortical brain injury, which involved the insertion of a needle into the somatosensory cortex of the brain, inducing localized structural brain damage with minimal secondary pathology. The results demonstrated that focal cortical brain injury before the onset of plaque deposition and mid-way into deposition did not alter Aβ plaque load post-injury. Furthermore, these studies indicated that APP/PS1 mice with established amyloidosis have the same microglial, astrocytic and synaptic responses to focal cortical brain injury as wild type mice, despite the presence of AD-related neuropathology. The second model of TBI utilized in this thesis was the lateral fluid percussion injury (LFPI) which produces widespread diffuse brain damage with evolving secondary pathology such as diffuse axonal injury (DAI). These studies demonstrated that LFPI prior to the onset of Aβ plaque deposition caused an increase in plaque load after injury, whereas LFPI during Aβ plaque deposition caused a decrease in plaque load postinjury. Thus, the results indicated that the stage of amyloidosis at the time of LFPI affected whether Aβ plaque deposition was enhanced or reduced in APP/PS1 mice after injury. Furthermore, as LFPI but not focal cortical brain injury altered Aβ plaque deposition after injury, the results indicate that diffuse TBI may be required for the modulation of Aβ plaque deposition after injury. DAI can result in impaired axonal transport and the intra-axonal accumulation of amyloid precursor protein (APP). Impaired axonal transport is caused by TBI-induced cytoskeletal damage and may be a potential mechanism for post-injury Aβ plaque formation. Neurofilaments are an integral part of the axonal cytoskeleton and undergo various pathological changes following TBI however, the role of NF in DAI and impaired axonal transport is unclear. Thus, the final study in this thesis investigated the effect of altering the NF cytoskeleton on the axonal response to injury. The results demonstrated that genetically altered mice lacking NF light gene showed an increased number of axonal APP accumulations, indicating higher levels of impaired axonal transport and thus DAI following LFPI. The research in this thesis provides insight into the effects of different types of TBI on Aβ plaque dynamics. The results indicated that diffuse but not focal TBI can alter Aβ plaque deposition after injury and that this modulation is dependent on the stage of amyloidosis at the time of injury. Lastly, this thesis demonstrated that the axonal cytoskeleton is important in the axonal response to TBI and may be a potential therapeutic target