Degree Granting Department
Alzheimer's disease, aneugenesis, atherosclerosis, calcium chelation, lipoproteins, membrane fluidity
Several lines of evidence link Alzheimer's disease (AD) to atherosclerosis (CVD), including that elevated low density lipoprotein (LDL)-cholesterol is a common risk factor. Development of genomic instability could also link the two diseases. Previous fluorescence in situ hybridization (FISH) analyses revealed a clonal expansion of aneuploid smooth muscle cells underlying atherosclerotic plaques. Likewise, cellular and mouse models of AD revealed tau-dependent mitotic defects and subsequent aneuploidy partly resulting from amyloid-beta (A&beta) interference with microtubule (MT) stability, and specific MT motors function. Moreover, AD patients develop aneuploid/hyperploid cells in brain and peripheral tissues, implicating similar mechanism that may lead to apoptosis and neurodegeneration.
This dissertation tested the hypothesis that elevated lipoproteins and cholesterol may contribute to genomic instability in AD and CVD and showed that: (1) treatment with oxidized LDL (OX-LDL), LDL and water soluble cholesterol, but not high density lipoprotein (HDL), induced chromosome mis-segregation, including trisomy and tetrasomy 12, 21, and 7 in human epithelial cells (hTERT-HME1), primary aortic smooth muscle cells, fibroblasts, mouse splenocytes and neural precursors; (2) LDL-induced aneuploidy may depend on a functional LDL receptor (LDLR), but not amyloid precursor protein (APP) gene; (3) fibroblasts and brain cells of patient with the mutation in the Niemann-Pick C1 gene (NPC1) characterized by impaired intracellular cholesterol trafficking and changed intracellular cholesterol distribution harbored trisomy 21 cells; (4) young wild-type mice fed high and low cholesterol diets developed aneuploidy in spleen but not in brain cells within 12 weeks; (5) like with the studies on A&beta-induced aneuploidy, calcium chelation reduced OX-LDL and LDL-mediated chromosomal instability; and (6) altering plasma membrane fluidity with ethanol attenuated OX-LDL and LDL-induced aneuploidy.
These results suggest a novel biological mechanism by which disrupted cholesterol homeostasis may promote both atherosclerosis and AD by inducing chromosome mis-segregation and development of aneuploid cells. Understanding the cause and consequence of chromosomal instability as a common pathological trait in AD and CVD may be beneficial to designing therapies relevant for both diseases.
Scholar Commons Citation
Granic, Antoneta, "The Role of Lipoproteins/cholesterol in Genomic Instability and Chromosome Mis-segregation in Alzheimer's and Cardiovascular Disease" (2011). Graduate Theses and Dissertations.