The Biochemical Effects of Tau and Zinc in A Tau Mouse Model
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Craven, Kristen Marie
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Abstract
Alzheimer’s disease is a neurodegenerative disease affecting millions worldwide. The hallmark signs are progressive memory loss, confusion, lack of spatial awareness, and changes in personality. This debilitating disease has no known cure and many drug treatments have failed the final stages of testing. Hyperphosphorylated tau is a key pathology within the Alzheimer’s disease brain as well as frontotemporal dementia, traumatic brain injury, and Parkinson’s disease. Using a transgenic mouse model that contains the human gene for tau protein (P301L), this study assessed the effects of excess chronic zinc supplementation on tau pathology. Zinc is an essential trace element that is vital for neuronal communication and can be found in high concentrations in the hippocampus, a structure that is affected in Alzheimer’s disease. Zinc has been shown to bind directly to tau and has also been shown to alter levels of phosphorylation. The pSer396 and Tau-5 antibodies were utilized in this study. The amount of phosphorylated tau protein at that site as well as the total amount of tau was semi-quantified (n = 4). Furthermore, Zinpyr-1 was used to semi-quantify the amount of free-zinc (n = 4). Finally, Thioflavin-S was utilized to determine the presence of tau tangles (n = 3). Results show that transgenic tau mice supplemented with zinc water demonstrated higher concentrations of phosphorylation at Ser396 whereas total tau levels remained steady. Furthermore, transgenic tau mice had significantly less free-zinc in the hippocampus compared to wildtype mice as determined by Zinpyr-1 staining, indicating that tau tangles may be sequestering the zinc. Finally, transgenic tau mice given zinc water demonstrated a higher number of tangles in the hippocampus at 7 months of age when compared with transgenic tau mice given standard lab water. These results show that zinc exacerbates tau pathology. Caution should be taken with regard to zinc supplementation, particularly in populations that are already at-risk of tauopathies such as Alzheimer’s disease.
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This thesis has been embargoed for 6 months and will not be available until June 2018 at the earliest.
Keywords
Tau, Western Blot, Zinc, Thioflavin-S, Zinpyr-I