The contribution of traumatic brain injury to Alzheimer’s disease progression
<p>The collective data from human and rodent studies indicate that a single traumatic brain injury (TBI) in healthy individuals can lead to an increased plaque burden, potentially accelerating the onset of Alzheimer's Disease (AD). However, there is limited research on the effects of TBI...
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| Other Authors: | |
| Format: | Thesis |
| Language: | English |
| Published: |
2023
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| _version_ | 1824458700748750848 |
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| author | Zainal Azman, JAB |
| author2 | Anthony, D |
| author_facet | Anthony, D Zainal Azman, JAB |
| author_sort | Zainal Azman, JAB |
| collection | OXFORD |
| description | <p>The collective data from human and rodent studies indicate that a single traumatic brain injury (TBI) in healthy individuals can lead to an increased plaque burden, potentially accelerating the onset of Alzheimer's Disease (AD). However, there is limited research on the effects of TBI in patients already diagnosed with AD. Gilbert et al. (2014) found that AD patients with a history of TBI (AD-TBI) experienced a more rapid progression of the disease, with a faster decline in cognitive abilities compared to AD patients without TBI. This suggests an interaction between AD pathology and TBI, accelerating disease progression. Yet, it remains unclear whether amyloid plaques, tau tangles, or both, are responsible for this outcome. Understanding the mechanisms behind this accelerated AD progression post-TBI is crucial, as it can guide interventions for AD-TBI patients. Notably, elderly AD patients are particularly susceptible to TBI, often due to falls, as shown in TBI epidemiology reports.</p>
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<p>This study hypothesizes that dysregulated systemic acute phase response (APR) following TBI in AD subjects is a key factor in hastening AD progression. In AD brains, existing conditions like plaques and/or tangles can keep microglia in a chronically active or "primed" state. Subsequent TBI can over-activate these primed microglia, leading to excessive cytokine secretion and abnormally high systemic APR. This could increase the mobilization of peripheral inflammatory cells and exacerbate brain injury, worsening AD. I tested this hypothesis using two transgenic AD mouse models, J20 and P301S, representing amyloid plaques and tau tangles, respectively, subjected to acute and chronic TBI. The J20-TBI model, compared to a wild-type TBI (WT-TBI) group, confirmed the two-hit hypothesis after acute contusion. 6-month-old (prodromal stage) and 12-month-old (AD dementia stage) J20 mice were used to study the impact of varying plaque burdens on APR. Mice in the prodromal stage showed a heightened APR compared to the AD dementia group. However, the P301S-TBI group did not display significant differences post-acute brain trauma compared to the WT-TBI control, suggesting a synergistic interaction between amyloid plaques and acute TBI, absent in tau tangles. Additionally, chronic TBI exposure in both J20-TBI and P301S-TBI groups resulted in negligible brain and systemic inflammatory profiles compared to the WT-TBI group.</p>
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<p>1H NMR coupled with OPLS-DA untargeted approach was performed in J20 vs WT groups to ascertain the top discriminatory metabolites as well as to generate a comprehensive J20 mutant metabolite profile covering pre-frontal cortex, hippocampus, liver, spleen, and serum. Citrate, glucose, and glutamine were discovered as the overlapping metabolites that are present in both central nervous system and periphery tissues which may hold the potential as peripheral biomarkers for AD. In conclusion, this study sheds light on a critical aspect of AD research, namely, the interplay between TBI and AD pathology. The findings suggest that in AD individuals, the dysregulated systemic APR triggered by TBI can exacerbate the progression of the disease, particularly in the presence of amyloid plaques. This insight not only provides a deeper understanding of the mechanisms underlying AD acceleration following TBI but also underscores the potential significance of targeting the APR pathway as an intervention strategy for AD patients with a history of TBI. These findings may pave the way for the development of novel therapies and the identification of peripheral biomarkers for AD, ultimately offering hope for improved clinical outcomes and better management of this devastating neurodegenerative condition, especially among the elderly population at higher risk of TBI.</p> |
| first_indexed | 2025-02-19T04:30:04Z |
| format | Thesis |
| id | oxford-uuid:7a47a3d8-f448-4fdc-887f-a393ac082a82 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2025-02-19T04:30:04Z |
| publishDate | 2023 |
| record_format | dspace |
| spelling | oxford-uuid:7a47a3d8-f448-4fdc-887f-a393ac082a822024-12-16T14:45:48ZThe contribution of traumatic brain injury to Alzheimer’s disease progressionThesishttp://purl.org/coar/resource_type/c_db06uuid:7a47a3d8-f448-4fdc-887f-a393ac082a82Alzheimer's diseaseAcute phase reactionBrain--wounds and injuriesEnglishHyrax Deposit2023Zainal Azman, JABAnthony, DJeans, A<p>The collective data from human and rodent studies indicate that a single traumatic brain injury (TBI) in healthy individuals can lead to an increased plaque burden, potentially accelerating the onset of Alzheimer's Disease (AD). However, there is limited research on the effects of TBI in patients already diagnosed with AD. Gilbert et al. (2014) found that AD patients with a history of TBI (AD-TBI) experienced a more rapid progression of the disease, with a faster decline in cognitive abilities compared to AD patients without TBI. This suggests an interaction between AD pathology and TBI, accelerating disease progression. Yet, it remains unclear whether amyloid plaques, tau tangles, or both, are responsible for this outcome. Understanding the mechanisms behind this accelerated AD progression post-TBI is crucial, as it can guide interventions for AD-TBI patients. Notably, elderly AD patients are particularly susceptible to TBI, often due to falls, as shown in TBI epidemiology reports.</p> <br> <p>This study hypothesizes that dysregulated systemic acute phase response (APR) following TBI in AD subjects is a key factor in hastening AD progression. In AD brains, existing conditions like plaques and/or tangles can keep microglia in a chronically active or "primed" state. Subsequent TBI can over-activate these primed microglia, leading to excessive cytokine secretion and abnormally high systemic APR. This could increase the mobilization of peripheral inflammatory cells and exacerbate brain injury, worsening AD. I tested this hypothesis using two transgenic AD mouse models, J20 and P301S, representing amyloid plaques and tau tangles, respectively, subjected to acute and chronic TBI. The J20-TBI model, compared to a wild-type TBI (WT-TBI) group, confirmed the two-hit hypothesis after acute contusion. 6-month-old (prodromal stage) and 12-month-old (AD dementia stage) J20 mice were used to study the impact of varying plaque burdens on APR. Mice in the prodromal stage showed a heightened APR compared to the AD dementia group. However, the P301S-TBI group did not display significant differences post-acute brain trauma compared to the WT-TBI control, suggesting a synergistic interaction between amyloid plaques and acute TBI, absent in tau tangles. Additionally, chronic TBI exposure in both J20-TBI and P301S-TBI groups resulted in negligible brain and systemic inflammatory profiles compared to the WT-TBI group.</p> <br> <p>1H NMR coupled with OPLS-DA untargeted approach was performed in J20 vs WT groups to ascertain the top discriminatory metabolites as well as to generate a comprehensive J20 mutant metabolite profile covering pre-frontal cortex, hippocampus, liver, spleen, and serum. Citrate, glucose, and glutamine were discovered as the overlapping metabolites that are present in both central nervous system and periphery tissues which may hold the potential as peripheral biomarkers for AD. In conclusion, this study sheds light on a critical aspect of AD research, namely, the interplay between TBI and AD pathology. The findings suggest that in AD individuals, the dysregulated systemic APR triggered by TBI can exacerbate the progression of the disease, particularly in the presence of amyloid plaques. This insight not only provides a deeper understanding of the mechanisms underlying AD acceleration following TBI but also underscores the potential significance of targeting the APR pathway as an intervention strategy for AD patients with a history of TBI. These findings may pave the way for the development of novel therapies and the identification of peripheral biomarkers for AD, ultimately offering hope for improved clinical outcomes and better management of this devastating neurodegenerative condition, especially among the elderly population at higher risk of TBI.</p> |
| spellingShingle | Alzheimer's disease Acute phase reaction Brain--wounds and injuries Zainal Azman, JAB The contribution of traumatic brain injury to Alzheimer’s disease progression |
| title | The contribution of traumatic brain injury to Alzheimer’s disease progression |
| title_full | The contribution of traumatic brain injury to Alzheimer’s disease progression |
| title_fullStr | The contribution of traumatic brain injury to Alzheimer’s disease progression |
| title_full_unstemmed | The contribution of traumatic brain injury to Alzheimer’s disease progression |
| title_short | The contribution of traumatic brain injury to Alzheimer’s disease progression |
| title_sort | contribution of traumatic brain injury to alzheimer s disease progression |
| topic | Alzheimer's disease Acute phase reaction Brain--wounds and injuries |
| work_keys_str_mv | AT zainalazmanjab thecontributionoftraumaticbraininjurytoalzheimersdiseaseprogression AT zainalazmanjab contributionoftraumaticbraininjurytoalzheimersdiseaseprogression |