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.
Highlights
High levels of dietary cholesterol and plasma LDL have been found to constitute a common risk factor for both atherosclerosis/ cardiovascular disease and for Alzheimer’s disease, but the mechanism(s) of this effect are incompletely understood [1,2]
We investigated the mechanism of this cell cycle defect and found that mutations in the presenilin 1 (PS1) and amyloid precursor protein (APP) genes that cause forms of AD (FAD) directly induce chromosome mis-segregation and up to 20% aneuploidy in lymphocytes and neurons of transgenic mice and in transfected cells
Metaphase chromosome analysis and fluorescence in situ DNA hybridization (FISH) were used to determine whether LDL/cholesterol increases the levels of total and chromosome specific aneuploidy in vivo: in mice fed a high cholesterol diet and in human Niemann-Pick patients with a mutation in the NPC1 gene, which is implicated in cholesterol trafficking and atherosclerosis but has not previously been associated with a defect in chromosome segregation, mitosis-specific epitopes have been observed in NCP1 brains [53,54] (Figure 1,2)
Summary
High levels of dietary cholesterol and plasma LDL have been found to constitute a common risk factor for both atherosclerosis/ cardiovascular disease and for Alzheimer’s disease, but the mechanism(s) of this effect are incompletely understood [1,2]. Atherosclerosis is characterized by localized accumulations of lipids, inflammatory cells, smooth muscle cells and calcified cell debris [3], while Alzheimer’s disease (AD) is characterized by aberrant oligomerization/polymerization of two misfolded proteins–extracellular amyloid-beta (Aß) assembled into amyloid deposits, and intracellular hyperphosphorylated tau assembled into neurofibrillary tangles [4,5,6]. We sought to determine whether there is a common pathogenic pathway by which cholesterol/LDL promotes the development of both atherosclerosis and Alzheimer’s disease. Cell Cycle Defects and Chromosome Mis-segregation in AD. Work from several laboratories confirmed and extended these results to buccal cells and brain neurons, with trisomy 21 constituting 10% of neurons in late stage AD brain [17,18,19,20,21]
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