The profile of caregivers to Alzheizner’s disease victims in Georgia was examined. The sample population consisted of 377 caregivers (20% of the registered members of the 16 Alzheimer’s Support Groups across the state). The findings revealed that, the majority of the caregivers are between the ages of 45 and 74 years old, they tend to be the spouse of the victim, live on a fixed income, and is experiencing emotional, physical and financial stress. The findings were analyzed utilizing tables and percent comparisons.

No description available.

Neurofibromatosis Type 2 (NF2) is a disorder of the nervous system, characterized by the formation of bilateral vestibular schwannoma tumors as well as meningioma and ependymoma tumors. Vestibular schwannomas are Schwann cell tumors that develop from the vestibulocochlear nerve and lead to deafness. NF2 is caused by mutations in the NF2 gene, encoding tumor suppressor protein merlin. NF2 tumors cause many symptoms depending on their location. The only NF2 treatments are surgery and radiosurgery which can impair nerve function, so alternative treatments such as drug-based therapies targeting pathways important for tumor formation, survival, and growth are needed. Targeting complementary pathways can be an effective way to overcome drug resistance. The Phosphoinositide 3 kinase (PI3K) and P21 activated kinases (PAK) pathways help control cellular processes related to tumor formation and are found dysregulated in merlin-deficient cells. Previous screening studies demonstrated synergistic effects of pictilisib (picti), an inhibitor of the PI3K pathway, and PF3758309 (PF), an inhibitor of PAK4 activity, on cell survival in merlin-null cells. To test the efficacy of this drug combination, a combination drug study was run using the NF2 allograft mouse peripheral nerve tumor model. Initial analyses revealed that these treatments and a combination may inhibit tumor growth. The purpose of this study was determining how PI3K and/or PAK inhibition by pictilisib and PF3758309 impact target protein levels in sciatic nerve NF2 allograft tumors. My role was analyzing tumors taken from the NF2 mice for targets proteins relevant to tumor growth and survival by conducting immunohistochemistry and ImageJ quantification. A secondary purpose was identifying possible deleterious side effects of drug treatment on healthy nerves with a qualitative assessment of contralateral sciatic nerves. Assessments support continued x evaluation of each drug for clinical use and show that the combination treatment can reduce cell proliferation and increase cell death.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1938. / Typescript. Includes abstract and vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references: leaves [100-102].

<p>Huntington’s disease (HD) is a neurodegenerative disorder caused by the expansion of a polyglutamine tract in the huntingtin protein. The huntingtin protein has many roles in vesicular and endocytic trafficking, which can be modified in HD cells. When mutant huntingtin is expressed in HD, protein levels of the huntingtin interacting protein, Huntingtin-associated protein of 40kDa (HAP40) are increased. This increase in HAP40 protein levels causes the formation of a complex between carboxyl terminal huntingtin, HAP40 and active Rab5 on the early endosome. This complex induces a switch from early endosomal movements on microtubules to movements on actin filaments, greatly reducing both the speed and distance of movement. The main objective of this research is to determine where the interaction occurs between huntingtin and HAP40 on the huntingtin protein. Here we show that HAP40 interacts with the amino terminus of huntingtin, specifically the first 17 amino acids (N17). In co-localization studies, we found that HAP40 co-localizes with the carboxyl terminal fragment of huntingtin corresponding to amino acids 2570-2634; however, GFP trap immunoprecipitation analysis revealed no interaction between the carboxyl terminal fragments of huntingtin and HAP40. An interaction was discovered between HAP40 and N17, which was then confirmed by far western blot. These results demonstrate that HAP40 interacts with N17. By identifying the interaction site between HAP40 and huntingtin, modifications can be explored to prevent the interaction of HAP40 with huntingtin. This would restore motility on microtubules reinstating fast, long-range movements of early endosomes.</p> / Master of Science (MSc)

University of Macau / Institute of Chinese Medical Sciences

Traumatic brain injury (TBI) is a devastating problem which stands as a leading cause of death and disability. The elderly is significantly affected by TBI, typically as the result of falls, and recovery is especially limited. This, in part, is associated with decreased tissue-specific stem cell regeneration and replacement of damaged cells in the aged brain. The diminished ability of the aged brain to recover is especially devastating after TBI, likely leading to permanent loss of sensory, motor, and cognitive functions. Studies have shown that the mature mammalian brain contains Neural Stem Cells (NSCs), found in specific regions of the brain, which can generate functional neurons during normal and pathological conditions. Two of those regions, the Dentate Gyrus (DG) of the hippocampus as well as the Subventricular Zone (SVZ) of the lateral ventricles, have proven to be niches for these multipotent NSCs. A key regulator in the maintenance of these NSCs is the Notch signaling pathway, shown to control proliferation, differentiation, and apoptosis of NSCs during development and throughout adulthood. In the current study, we assessed the regulatory mechanisms that drive the regenerative functions of NSCs in a neuropathological state following TBI. Using the Lateral Fluid Percussion Injury model, we analyzed the diffuse effects of the injury response on 3-month old male Sprague-Dawley rats. Immediately following TBI, Notch agonist, antagonist or vehicle was infused into the lateral ventricle for 7 days to assess the role of Notch signaling on neural stem cell proliferation/survival and neurogenesis at 30 days post-TBI. Dividing cells during infusion time were labeled with BrdU via single daily intraperitoneal injections for 7 days. Animals were sacrificed at 30 days post-injury and brain tissues were processed then immunolabeling for BrdU and Doublecortin. We found a higher number of BrdU-positive cells in the FPI+Notch1 agonist group when compared to Sham and FPI+Jagged-1 Fc antagonist groups in the contralateral granular zone. A significant increase in proliferation/survival was also seen in FPI+Notch1 versus Sham/FPI+Jagged-1 Fc and for FPI+Vehicle versus Sham animals in both the ipsilateral and contralateral hilus. DCX immunolabeling did not establish a significant difference in FPI+Notch1 compared to Sham animals, nor across any other groups, which is consistent with what we know of activation of the Notch pathway. Our results demonstrate that Notch1 signaling is directly involved in cellular proliferation/survival of NSCs in the DG following TBI at 30 days post-injury, but further work must be done to understand the fate of these cells. Thus, drug treatment targeting Notch1 signaling could serve as a potential therapeutic target following TBI to preserve NSCs and limit long-term cognitive deficits.

No description available.

β-methylamino-L-alanine (BMAA) is thought to be a contributing factor of Amyotrophic Lateral Sclerosis-Parkinsonism Dementia Complex (ALS/PDC). It has been shown that the levels of toxin ingestion by humans are too low to cause disease. However, it has recently been theorized that this toxin is bioaccumulated within cells. Via a process of slow release from this reservoir, the BMAA is able to bring about neurotoxicity. Mechanisms of uptake and bioaccumulation of BMAA have been proposed in several publications; however the mechanism of protein incorporation of BMAA has not yet been identified. Identifying suitable model systems would be a prerequisite in order for future studies on BMAA protein incorporation. Three specific models were therefore chosen for investigation; mammalian cell lines including C2C12 and HT29, a prokaryotic (E. coli) expression system and yeast cells. The cytotoxity of BMAA was established for the mammalian cell lines and further investigation of BMAA incorporation into cellular proteins was performed on all three above mentioned models. Samples were run on HPLC-MS in order to determine uptake of BMAA into cells or lack thereof. Results indicate negligible cytotoxicity as measured by MTT and CellTitre Blue assays, limited uptake and protein incorporation of BMAA within the prokaryotic model and insignificant uptake of BMAA by yeast cells. Although the uptake of BMAA in the prokaryotic model was not extensive, there was indeed uptake. BMAA was not only taken up into the cells but was also observed in inclusion body protein samples after hydrolysis. After further investigation and use, this model could very well provide researchers with information pertaining to the mechanism of association of BMAA with proteins. Although the other models provided negative results, this research was valuable in the sense that one can narrow down the number of possible model systems available. Also, in seeking models for studying protein association/incorporation, the use of the final target cell is not relevant or necessary as the purpose of the research was to identify a model system in which the mechanism of protein association/incorporation can, in future, be studied.

published_or_final_version / abstract / Medicine / Master / Doctor of Medicine