title: Mitotic spindle defects and chromosome mis-segregation induced by LDL/cholesterol-implications for Niemann-Pick C1, Alzheimer's disease, and atherosclerosis.
abstract: Elevated low-density lipoprotein (LDL)-cholesterol is a risk factor for both Alzheimer's disease (AD) and Atherosclerosis (CVD), suggesting a common lipid-sensitive step in their pathogenesis. Previous results show that AD and CVD also share a cell cycle defect: chromosome instability and up to 30% aneuploidy-in neurons and other cells in AD and in smooth muscle cells in atherosclerotic plaques in CVD. Indeed, specific degeneration of aneuploid neurons accounts for 90% of neuronal loss in AD brain, indicating that aneuploidy underlies AD neurodegeneration. Cell/mouse models of AD develop similar aneuploidy through amyloid-beta (Aß) inhibition of specific microtubule motors and consequent disruption of mitotic spindles. Here we tested the hypothesis that, like upregulated Aß, elevated LDL/cholesterol and altered intracellular cholesterol homeostasis also causes chromosomal instability. Specifically we found that: 1) high dietary cholesterol induces aneuploidy in mice, satisfying the hypothesis' first prediction, 2) Niemann-Pick C1 patients accumulate aneuploid fibroblasts, neurons, and glia, demonstrating a similar aneugenic effect of intracellular cholesterol accumulation in humans 3) oxidized LDL, LDL, and cholesterol, but not high-density lipoprotein (HDL), induce chromosome mis-segregation and aneuploidy in cultured cells, including neuronal precursors, indicating that LDL/cholesterol directly affects the cell cycle, 4) LDL-induced aneuploidy requires the LDL receptor, but not Aß, showing that LDL works differently than Aß, with the same end result, 5) cholesterol treatment disrupts the structure of the mitotic spindle, providing a cell biological mechanism for its aneugenic activity, and 6) ethanol or calcium chelation attenuates lipoprotein-induced chromosome mis-segregation, providing molecular insights into cholesterol's aneugenic mechanism, specifically through its rigidifying effect on the cell membrane, and potentially explaining why ethanol consumption reduces the risk of developing atherosclerosis or AD. These results suggest a novel, cell cycle mechanism by which aberrant cholesterol homeostasis promotes neurodegeneration and atherosclerosis by disrupting chromosome segregation and potentially other aspects of microtubule physiology.
authors.affiliation: Department of Neurology and Linda Crnic Institute for Down Syndrome, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: Antoneta
authors.initials: A
authors.lastname: Granic
authors.forename: Huntington
authors.initials: H
authors.lastname: Potter
mesh_terms: D000328:Adult; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000782:Aneuploidy; D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology*; D002118:Calcium / Q000378:metabolism; D016022:Case-Control Studies; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D008078:Cholesterol, LDL / Q000494:pharmacology*; D020090:Chromosome Segregation / Q000187:drug effects*; D004314:Down Syndrome / Q000378:metabolism / Q000473:pathology; D000431:Ethanol / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D008560:Membrane Fluidity / Q000187:drug effects; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D052556:Niemann-Pick Disease, Type C / Q000378:metabolism / Q000473:pathology*; D008941:Spindle Apparatus / Q000187:drug effects / Q000378:metabolism*; D055815:Young Adult
chemical_list: D016229:Amyloid beta-Peptides; D008078:Cholesterol, LDL; D000431:Ethanol; D002118:Calcium