Date of Award
Doctor of Philosophy in Interdisciplinary Neuroscience
Nasser H. Zawia
Alzheimer’s Disease (AD) has a complicated pathology with many potential etiologies. In patients, a diagnosis of AD is confirmed at the time of autopsy by the presence of two major pathological hallmarks: the amyloid beta plaque (Aβ plaque) and the neurofibrillary tangle (NFTs). The late-onset (LOAD) form of this disease has no clear genetic etiology, with the exception of an increased risk of carrying the APOE4 allele. Therefore, research has focused on identifying environmental risk factors in its etiology. Our lab has a legacy of studying environmental exposure to lead (Pb) during early development. We have shown in previous publications that exposure to Pb during early life results in the upregulation in a number of key genes in the amyloid and tau pathways directly related to the development of the characteristic hallmarks of AD.
In this dissertation, Manuscript I was a review of the literature related to Pb exposure in both children and adults, and the role Pb has in neurodegenerative diseases, either by workplace exposures or by developmental basis of diseases. The focus of the review was also to present evidence from our work and others to suggest the mechanism by which these changes occur, via potential epigenetic pathways.
Manuscript II was aimed to investigate the involvement of epigenetic pathways in the developmental model of Pb exposure, in which (wild-type mice were exposed to 0.2% Pb from PND 1 and 20 Western blot and RT-PCR analysis were performed for a number of key epigenetic marks and regulators across the lifespan in the cortex of mice developmentally exposed to Pb. Alterations in a number of key mediators involved in DNA methylation were identified across the lifespan, as well as specific alterations in histone marks involved in both repression (H3K27me3) and activation (H3K9Ac, H3K4me2) pathways. Activating histone proteins were globally downregulated in the cortex whereas the repression mark was increased at the end of life.
Manuscript III, utilized the innovative technique of ChIP-seq to identify H3K9Ac binding peaks in the mouse genome across the lifespan of developmentally Pb exposed mice. Unique peaks were present in the Pb exposed animals, with an emphasis on peaks in the promoter were reported. Of the genes affected, it was found many were associated with AD pathology by utilizing the Kegg’s pathway thingy, specifically it was shown that genes have acetylation islands in or near the promoter that were differentially acetylated in Pb exposed mice later in life. Therefore, by these findings show that epigenetic regulation, specifically by H3K9Ac, could be a potential mechanism by which AD-related genes become upregulated late in life.
Eid, Aseel, "Epigenetic Pathways Involved in Response to Lead (PB) Exposure in the Aging Brain: Relevance to Alzheimer's Disease" (2016). Open Access Dissertations. Paper 511.
Available for download on Friday, November 23, 2018