Alzheimer’s disease is a progressive neurodegenerative disorder and the most common form of dementia. Like many neurological
disorders, Alzheimer’s disease has a sex-biased epidemiological profile, affecting approximately twice as many women as men. The cause of
this sex difference has yet to be elucidated. To identify molecular correlates of this sex bias, we investigated molecular sex differences
in the hippocampus of healthy female and male mice at 1, 2, and 4 months of age. This analysis identifies a host of genes that display
sex-biased expression in the developing mouse hippocampus, many of which are heat shock proteins. Using this dataset as a baseline, we
investigated molecular pathology in both sexes using the 5XFAD transgenic mouse model of Alzheimer’s disease. We profiled the
transcriptome of the mouse hippocampus during early stages of disease development with RNA-sequencing. To supplement our transcriptomic
analysis, we performed a series of liquid-chromatography mass spectrometry analyses of protein abundance. This proteomic investigation was
refined by an extensive methods-oriented analysis of sample fractionation. The analysis of 5XFAD transgenic mice reveals pathological
differences in transcript abundance as early as 2 months of age, prior to observable plaque deposition. At 4 months of age, we detect
wide-spread up regulation of transcripts associated with immune function in diseased animals. Interestingly, our data indicate that female
transgenic mice show a stronger disease phenotype than their male counterparts as measured by number of differentially expressed genes. We
also find elevated expression of the 5XFAD transgenes in females relative to males, which likely accounts for a portion of sex-biased
molecular pathology observed in this dataset. Taken together, our analyses identify both innate molecular sex differences in the rodent
brain, as well as molecular correlates of sex-biased disease features. The findings enhance our understanding of neural sex-differences,
and present potential candidate biomarkers for pharmacological intervention for Alzheimer’s disease. / A Dissertation submitted to the Department of Biomedical Sciences in partial fulfillment of the
Doctor of Philosophy. / Fall Semester 2016. / November 10, 2016. / Includes bibliographical references. / Richard S. Nowakowski, Professor Directing Dissertation; Thomas Houpt, University Representative;
Michelle Arbeitman, Committee Member; Brian Inouye, Committee Member; James Olcese, Committee Member.
| Identifer | oai:union.ndltd.org:fsu.edu/oai:fsu.digital.flvc.org:fsu_405668 |
| Contributors | Bundy, Joseph L. (Joseph Ligon) (authoraut), Nowakowski, Richard S. (professor directing dissertation), Houpt, Thomas (university representative), Arbeitman, Michelle N. (committee member), Inouye, Brian D. (committee member), Olcese, James (committee member), Florida State University (degree granting institution), College of Medicine (degree granting college), Department of Biomedical Sciences (degree granting departmentdgg) |
| Publisher | Florida State University, Florida State University |
| Source Sets | Florida State University |
| Language | English, English |
| Detected Language | English |
| Type | Text, text |
| Format | 1 online resource (130 pages), computer, application/pdf |
| Rights | This Item is protected by copyright and/or related rights. You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s). The copyright in theses and dissertations completed at Florida State University is held by the students who author them. |
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