Changes in amyloid precursor protein and Tau pathology after diffuse traumatic brain injury in the mouse
(2020) MOBN03 20192Degree Projects in Molecular Biology
- Abstract
- Traumatic brain injury (TBI) is a common cause of morbidity and mortality in young individuals. Following TBI, the initial injury caused by the head impact is exacerbated by a complex cascade of secondary injury factors leading to increased tissue loss. TBI is an established risk factor for neurodegenerative disorders including Alzheimer disease (AD). In long-term survivors of TBI, increased aggregation of beta-amyloid (Aβ) and hyperphosphorylated Tau into neurofibrillary tangles (NFTs) is common. Moreover, early post-TBI, increased Tau expression, as well as Aβ plaques, are observed.
We hypothesized that a TBI model producing wide-spread axonal injury (the central fluid percussion injury model, cFPI) in mice results in increased... (More) - Traumatic brain injury (TBI) is a common cause of morbidity and mortality in young individuals. Following TBI, the initial injury caused by the head impact is exacerbated by a complex cascade of secondary injury factors leading to increased tissue loss. TBI is an established risk factor for neurodegenerative disorders including Alzheimer disease (AD). In long-term survivors of TBI, increased aggregation of beta-amyloid (Aβ) and hyperphosphorylated Tau into neurofibrillary tangles (NFTs) is common. Moreover, early post-TBI, increased Tau expression, as well as Aβ plaques, are observed.
We hypothesized that a TBI model producing wide-spread axonal injury (the central fluid percussion injury model, cFPI) in mice results in increased expression of amyloid precursor protein (APP), that upon cleavage may produce neurotoxic Aβ species, and hyperphosphorylation of tubulin associated unit (hpTau). We investigated protein levels of APP together with Tau detrimental epitopes and gene expression following cFPI at four different time points (2, 7, 14 and 30 days post-injury; dpi) while focusing predominately on the acute phase (2 and 7 dpi). When compared to sham (injured control), brain-injured mice had increased APP levels at 2 and 7 dpi, decreasing at 14 and 30 dpi following cFPI. Using immunochemistry (IHC) staining, APP was systematically present in cortical axons at 2 and 7 dpi compared to sham, although protein levels were not changed. We also observed a 2 fold hyperphosphorylation of Tau at Ser202 /Thr205 (AT8), while not at the Thr231 (AT180) site in the cortex following TBI.
In contrast, a downregulation of the microtubule-associated protein Tau (MAPT) gene was observed at 2 dpi that was increased by 7 dpi when compared to controls. Our data indicate that TBI in mice, using a diffuse injury model producing extensive axonal and white matter injury, alters gene and protein levels of factors associated with neurodegeneration and dementias. Further studies are needed to establish whether these early changes persist or are altered with longer post-injury time points and whether these changes develop into hpTau and/or Aβ aggregates. (Less) - Popular Abstract
- Changes in amyloid precursor protein and Tau pathology after diffuse traumatic brain injury in the mouse
Traumatic brain injury (TBI) caused for instance by motor vehicle accidents, falls and during sports, is a common cause of mortality in young individuals. From the hit to the head, the brain tissue may be injured. The brain injury caused by the hi (the primary injury) is commonly worsened by complex cascades of secondary injury factors, leading to increased tissue loss. Also, TBI is an established risk factor for dementias like Alzheimer disease (AD). In AD, two proteins characterize the disease, accumulation of beta-amyloid (Aβ) protein and Tau(hpTau) protein into neurofibrillary tangles (NFTs). These proteins are also found in... (More) - Changes in amyloid precursor protein and Tau pathology after diffuse traumatic brain injury in the mouse
Traumatic brain injury (TBI) caused for instance by motor vehicle accidents, falls and during sports, is a common cause of mortality in young individuals. From the hit to the head, the brain tissue may be injured. The brain injury caused by the hi (the primary injury) is commonly worsened by complex cascades of secondary injury factors, leading to increased tissue loss. Also, TBI is an established risk factor for dementias like Alzheimer disease (AD). In AD, two proteins characterize the disease, accumulation of beta-amyloid (Aβ) protein and Tau(hpTau) protein into neurofibrillary tangles (NFTs). These proteins are also found in brain tissue of patients who have suffered a TBI many years previously. We argue that if the mechanisms to why Aβ and Tau increase in the brain after TBI were known, a treatment that reduces the risk of dementia could be developed.
Here, we used an animal (mice) model of TBI that produces a wide-spread injury to axons, the long processes of nerve cells (the model is called the central fluid percussion injury model, cFPI). We studied if TBI resulted in increased brain levels of amyloid precursor protein (APP), that give rise to Aβ, and hpTau. We measured the protein levels and gene expression up to 30 days after the brain injury. Our main focus was on changes in the first week after the injury.
Our main findings are that the level of APP (which then cause Aβ production) are increased in the brain during the first week. While the gene for tau was decreased early following the injury, after one week it was increased in the injured brain. Some of the tau proteins (there are several) were also increased.
Our results show that TBI rapidly increases proteins that are typically seen in patients with dementia. Injury to axons seems to be the cause of the production of dementia-like proteins.
It is likely that these changes are negative for the recovery of the injured brain. These changes happen in the first week after injury, so any treatment must be given early to the patient. These results are important to understand the relationship of brain injury to human dementia and other diseases of neurodegeneration.
Master’s Degree Project in Molecular Biology, 60 credits, 2020.
Department of Biology, Lund University
Advisor: Niklas Marklund
Neurosurgery, Lund University (Less)
Please use this url to cite or link to this publication:
http://lup.lub.lu.se/student-papers/record/9032311
- author
- Bloju, Octavian Marian
- supervisor
- organization
- course
- MOBN03 20192
- year
- 2020
- type
- H2 - Master's Degree (Two Years)
- subject
- language
- English
- id
- 9032311
- date added to LUP
- 2020-11-24 12:45:52
- date last changed
- 2021-05-03 07:58:57
@misc{9032311,
abstract = {{Traumatic brain injury (TBI) is a common cause of morbidity and mortality in young individuals. Following TBI, the initial injury caused by the head impact is exacerbated by a complex cascade of secondary injury factors leading to increased tissue loss. TBI is an established risk factor for neurodegenerative disorders including Alzheimer disease (AD). In long-term survivors of TBI, increased aggregation of beta-amyloid (Aβ) and hyperphosphorylated Tau into neurofibrillary tangles (NFTs) is common. Moreover, early post-TBI, increased Tau expression, as well as Aβ plaques, are observed.
We hypothesized that a TBI model producing wide-spread axonal injury (the central fluid percussion injury model, cFPI) in mice results in increased expression of amyloid precursor protein (APP), that upon cleavage may produce neurotoxic Aβ species, and hyperphosphorylation of tubulin associated unit (hpTau). We investigated protein levels of APP together with Tau detrimental epitopes and gene expression following cFPI at four different time points (2, 7, 14 and 30 days post-injury; dpi) while focusing predominately on the acute phase (2 and 7 dpi). When compared to sham (injured control), brain-injured mice had increased APP levels at 2 and 7 dpi, decreasing at 14 and 30 dpi following cFPI. Using immunochemistry (IHC) staining, APP was systematically present in cortical axons at 2 and 7 dpi compared to sham, although protein levels were not changed. We also observed a 2 fold hyperphosphorylation of Tau at Ser202 /Thr205 (AT8), while not at the Thr231 (AT180) site in the cortex following TBI.
In contrast, a downregulation of the microtubule-associated protein Tau (MAPT) gene was observed at 2 dpi that was increased by 7 dpi when compared to controls. Our data indicate that TBI in mice, using a diffuse injury model producing extensive axonal and white matter injury, alters gene and protein levels of factors associated with neurodegeneration and dementias. Further studies are needed to establish whether these early changes persist or are altered with longer post-injury time points and whether these changes develop into hpTau and/or Aβ aggregates.}},
author = {{Bloju, Octavian Marian}},
language = {{eng}},
note = {{Student Paper}},
title = {{Changes in amyloid precursor protein and Tau pathology after diffuse traumatic brain injury in the mouse}},
year = {{2020}},
}