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The behavioural effects of stress and aluminium toxicity on a mouse model of amyotrophic lateral sclerosis parkinsonism-dementia complex

University of British Columbia

Background: The etiology of idiopathic neurodegenerative diseases such as Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS) remain unclear. However, it is likely that some combination of genetic susceptibility, environmental toxins and lifestyle factors precipitate onset in an aging-dependent manner. In order to better understand these complex relationships, this thesis investigated two multi-hit hypotheses. These multi-hit hypotheses involved combining a toxin induced neurodegenerative murine model with an environmental factor, aluminum, and separately with a lifestyle factor, stress. The model of progressive age-related neurodegenerative disease that was used to assess these multi-hit hypotheses was the stigmasterol beta-D-glucoside (SG) dietary toxin mouse model of amyotrophic lateral sclerosis – parkinsonism dementia complex (ALS-PDC). The SG dietary toxin is found in the cycad tree, a type of which is native to Guam, and whose ingestion is believed responsible for the unusually high levels of neurodegenerative disease which were found there in the mid-twentieth century. The inclusion of water-borne aluminum as part of a multi-hit model was based on previous research epidemiologically linking high levels of aluminum in water and soil in Guam to the ALS-PDC phenotype. The lifestyle factor which was applied to the ALS-PDC model was exogenously administered chronic stress, which in humans can result in neurodegeneration and impaired neurogenesis. The prediction was that these two hits, one environmental and one lifestyle related, would exacerbate the behavioural ALS-PDC symptoms. Results: The combination of water-borne aluminum with the ALS-PDC murine model did not lead to behavioural motor impairments beyond what was seen with aluminum alone. However, anxiogenic phenotypes were observed for both aluminum and the combination of aluminum and the SG toxin relative to controls. The application of chronic restraint stress to the ALS-PDC murine model revealed a significant reduction in gait disturbances relative to what was seen with restraint stress alone. Conclusion: The results suggest that both restraint stress and aluminum can mediate behavioural outcomes in the SG induced murine model of ALS-PDC. However, the high degree of variability within the results suggests that, as is observed with clinical cases of age-related neurodegenerative disease, individual susceptibility is a core determinant of disease progression.

Text

2015-07-06

Attribution-NonCommercial-NoDerivs 2.5 Canada

http://hdl.handle.net/2429/54004

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/2.5/ca/