Neurodegenerative diseases are highly multifaceted. Despite their heavy burden, treatment options are limited and our understanding of their molecular triggers even less so. In this thesis, I focus on the pathogenesis of Alzheimer’s Disease (AD) due to familial, sporadic and environmental causes. Previous research shows that early AD stages are characterized by upregulated functionality of mitochondria-associated endoplasmic reticulum (ER) membranes. These “MAM” domains of the ER are dynamic contacts between the ER and mitochondria distinguished by a unique lipid composition equivalent to a lipid raft. These sites cluster a specific set of metabolic enzymes that regulate cellular lipid uptake, trafficking and turnover. We find that cleavage of the amyloid precursor protein at MAM domains is intimately involved in MAM regulation through localization of its C-terminal fragment of 99 a.a., C99, to MAM regions. C99 upregulates MAM functionality by promoting cholesterol uptake and trafficking to the ER for esterification, observable in both familial and sporadic AD samples. Here, we recapitulated these phenotypes in a mouse model of an environmental AD trigger: traumatic brain injury (TBI). Through biochemical, transcriptional and lipidomic analyses, we observed MAM functionality to be upregulated following a single brain injury. This was determined by assessment of phospholipid synthesis and cholesterol esterification. This correlated with increased deposition of C99 in MAM domains as well as cell type-specific lipidomic alterations. Specifically, cholesterol esterification was predominant in microglia, triglyceride elevations were predominant in microglia and astrocytes, and polyunsaturated phospholipid elevations were predominant in neurons. We hypothesize that, in the acute phase, MAM upregulation serves to promote lipid synthesis for tissue repair. However, if these phenotypes are sustained (such as after multiple injuries), cognitive functions dependent on neuronal functionality could become compromised. Altogether, we propose that the induction of AD pathogenesis following brain injury may arise from chronic upregulation of MAM activities. This work advances our understanding of neurodegenerative disease etiology.

Indiana University-Purdue University Indianapolis (IUPUI)

Traumatic brain injury (TBI) is a prevalent condition worldwide with 1.7 million incidences in the U.S. alone. A range of clinical outcomes have been reported post TBI, including dementia, memory loss, and impaired balance and coordination. The lack FDA approved treatments for TBI drives the need for improved prevention and therapeutic strategies. Finite element (FE) models of brain injury mechanics can be used to advance these efforts. These computational models require appropriate constitutive properties in order to predict accurate brain tissue response to injury loading. Suitable experimental models need to be implemented to match the resolution and computational power of FE models. The first aim of this thesis was to characterize the mechanical properties of brain tissue. Here, human, porcine, and rat brain tissue mechanical responses to multistep indentation of increasing strains up to 30% strain were recorded. We tested whether the quasilinear theory of viscoelasticity (QLV) was required to capture the mechanical behavior of brain tissue, but observed that linear viscoelasticity was sufficient under the loading condition applied. Using this fitting model, brain tissue stiffness was found to be dependent on anatomical region, loading direction, age, sex and species to varying degrees. This analysis elucidated factors that affect brain tissue injury mechanics and can be used to improve the accuracy of FE models of brain tissue deformation to predict a biofidelic response to TBI. There is growing evidence linking TBI to pathologies leading to increased risk of neurodegeneration, like tauopathies. However better understanding of these underlying mechanisms is still needed. In our study, we utilized a custom shock tube design to induce blast TBI (bTBI). To isolate the effect of bTBI-induced tau pathology, tau was extracted from sham and shockwave exposed mice 24 hours post injury, referred to as sham and blast tau respectively. We showed that bTBI increased phosphorylation of tau and its propensity to oligomerize. Treatment with blast tau resulted in impaired behavior in mice as well as reduced long term potentiation (LTP) in acute hippocampal slices. Treatment with brain isolate from shockwave exposed tau knockout mice did not exhibit altered behavior or LTP response, eliminating the possibility that any confounding factor in the blast tau preparation was responsible for the impaired outcome. Administration of de-oligomerized blast tau prevented these cognitive impairments, suggesting that toxic effect of blast tau was attributed to its oligomeric form. Here we showed that blast injury can initiate cascades in tau pathology and exposure to this progression results in worsened neurological outcome. Tau phosphorylation is mainly regulated by protein phosphatase 2A (PP2A), whose activity can be altered by leucine carboxyl methyltransferase 1 (LCMT-1) and protein phosphatase methylesterase 1 (PME-1). We sought to leverage this mechanism by infusing LCMT-1 and PME-1 transgenic mice with sham and blast tau. LCMT-1 overexpression prevented behavior and LTP deficits induced by oligomeric blast tau. Furthermore, PME-1 overexpression worsened behavior and LTP response at subthreshold doses of oligomeric blast tau. Together, this illustrated the ability of these two enzymes to regulate the response to exposure of bTBI-induced pathogenic forms of tau. This study indicates the potential of targeting PP2A activity as a viable strategy for therapeutic intervention. In conclusion, this research expands our understanding of the complexity of brain tissue injury mechanics to inform computational models of TBI, illustrates the deleterious effect of pathogenic forms of tau induced by blast injury on cognitive function, and presents a potential target mechanism for the investigation of therapeutic strategies.

No description available.

published_or_final_version / abstract / Paediatrics and Adolescent Medicine / Master / Master of Philosophy

Traumatic Brain Injury (TBI) is a disability resulting in functional impairments and heightened dependence on others. Family members of persons with TBI can assume added responsibilities during the adjustment to the disability and rehabilitation process, placing strain on the family system. Community re-integration is a primary goal of the rehabilitation process for persons with TBI as this is a step in developing autonomy and promoting independence and productive activity throughout different areas of the person's life (e.g., work, social networks, and home life). This study was designed to examine predictors of community re-integration outcomes of TBI survivors and empirically test the resiliency model of family stress, adjustment, and adaptation while incorporating family needs by surveying caregiving family members. Specific aims of the study include validating relationships of the resiliency model with individual and family outcomes in adaptation and supporting future recommendations for healthcare providers working with families with members with TBI. / by Julianne Agonis. / Thesis (Ph.D.)--Florida Atlantic University, 2012. / Includes bibliography. / Electronic reproduction. Boca Raton, Fla., 2012. Mode of access: World Wide Web.

Thesis (M. A. (Psychology)) --University of Limpopo, 2017 / This study investigated the perceptions of African families of TBI. Caregivers and TBI victims were given the opportunity to talk about their TBI perceptions. The study revealed that people’s knowledge of TBI is not good. This is proven by the way in which the participants understood and explained the conditions the victims found themselves in, after the accidents and how their family members are. Findings reveal that culture does play a vital role in the perceptions of African people. The study illustrates that the perceptions are culturally-rooted. The study interviewed five individuals (n=5) with TBI and a total of nine caregivers (n=9) were interviewed. A total of fourteen (n=14) participants were interviewed. The study reveals that the causes of TBI were attributed a number of things. According to the participants TBI is caused by witchcraft, the will of God and ancestors. The study also helped highlight the beliefs and the cultural system of Africans. It also explained the reality of an African. The Afrocentric theory helped shape the study as it helped in explaining the importance of an Africans’ view. The Afrocentric theory postulates that Africans have a different reality from that of Westerns and it has been proven by the findings. Although the participants were told about TBI by the doctors, they still had their own explanations and attributions to the problem.

With over 50,000 deaths and 80,000 disorders annually in the United States resulting from traumatic brain injury (TBI), there is a demand for improved therapeutic strategies. Cell transplantation offers the potential to treat TBI by targeting multiple mechanisms in a sustained fashion. However, efforts are needed to improve survival and integration of transplanted cells, and ultimately enhance functional recovery. Using tissue engineering strategies, we aimed to mimic key aspects of fetal tissue grafts by combining neural stem cells with a fibronectin or laminin based scaffold that could be delivered to the injured brain in a minimally invasive fashion. We found that the incorporation of extracellular matrix proteins into a cell transplantation paradigm led to improved donor cell survival and restored cognitive ability for treated animals. To begin to examine how fibronectin and laminin mediate these improvements, we first examined the endogenous role of these two proteins in the injured brain. Using a clinically-relevant model of TBI, we found both proteins are increased in the injured brain at acute time points. The spatial localization of fibronectin and laminin with specific support cells in the brain suggests a role for these proteins in repair, warranting further investigation. Using conditional plasma fibronectin knockout animals, we found that fibronectin is neuroprotective to the traumatically injured brain. Specifically, injured fibronectin knockout animals had more severe motor and cognitive deficits, increased cell death, and decreased retention of phagocytic cells compared to injured wild type animals. Thus, we have identified novel therapeutic treatments for TBI which utilize tissue engineered transplants and/or exploit endogenous repair mechanisms for fibronectin.

There has been much debate about whether shallow water diving , in the absence of neurological insult , can lead to cognitive deficits. The aim of this study was to investigate possible neuropsychological effects on two groups of divers , without any known history of decompression illness, who represent opposite ends of the spectrum of diving practice (rescue divers and sport divers) , and to compare them with a non-diving control group. 17 rescue divers , 17 non-diving controls and 15 sport divers were recruited. The groups were matched for age, but not for education. The two diving groups were comparable in terms of diving history. Results of neuropsychological testing indicated that the rescue diving group was not significantly different from the control group, suggesting that rescue diving under controlled conditions is comparatively safe. The sport diver group performed significantly worse than controls on a test of verbal reasoning (Comprehension, SAWAIS-R) and on a measure of word fluency (Controlled Oral Word Initiation Test), suggesting the possibility that risky diving practices may lead to decrements in frontal lobe functioning. Another possibility is that global decrements occur, but that the tests of frontal lobe functioning were more sensitive to mild deficits in functioning. This contention is tentative, and further research into frontal lobe functioning of divers should be conducted. Sport divers are recommended to follow safe diving practices and use dive profiles that avoid bubbling in order to prevent cognitive damage. VI / Thesis (M.A.)-University of Natal, Pietermaritzburg, 2002.

Large neocortical lesions, such as hemidecortication, are detrimental for motor and cognitive skills. This thesis investigates the effect of age at the time of lesion on functional outcome. Attempts were then made to improve the outcome by using two simple treatments, tactile stimulation and Fibroblast Growth Factor-2 (FGF-2). The functional outcome of animals was measured using a series of behavioural tests (Morris water task, skilled reaching, forelimb placing during spontaneous vertical exploration, and the sunflower seed task). A qualitative difference was noted between animals that received hemidecortication at post natal day ten (P 10) versus animals that received a hemidecortication in adulthood (postnatal day, P 90). When the tactile stimulation treatment was used on animals that received P 10 hemidecortication, cognitive and motor improvements were noted. The same was not true for injections of FGF-2. When given after P 10 hemidecortication, this treatment impaired the cognitive abilities of rats in the Morris water task. There are two main points from this project: 1) overall functional recovery is not better or worse but simply different based on the age at which the trauma occurred and 2) treatments have varied success with different types of brain injury. / x, 123 leaves ; 29 cm.