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Hfe Gene Variants and Dysregulation of Cholesterol and Iron Metabolism in Alzheimer Disease and Cancer

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Hfe Gene Variants and Dysregulation of Cholesterol and Iron Metabolism in Alzheimer Disease and Cancer The Pennsylvania State University The Graduate School College of Medicine HFE GENE VARIANTS AND DYSREGULATION OF CHOLESTEROL AND IRON METABOLISM IN ALZHEIMER DISEASE AND CANCER A Dissertation in Molecular Medicine by Fatima Ghazanfar Ali-Rahmani © 2012 Fatima Ali-Rahmani Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy December 2012 The dissertation of Fatima Ali-Rahmani was reviewed and approved* by the following: James R. Connor Distinguished Professor of Neurosurgery, Neural & Behavioral Sciences, and Pediatrics Vice Chair of Neurosurgery Dissertation Advisor Chair of Committee Cara-Lynne Schengrund Emeritus Professor of Biochemistry and Molecular Biology Ian Simpson Professor of Neural & Behavioral Sciences Patricia S. Grigson Professor of Neural & Behavioral Sciences Jong K. Yun Associate Professor of Pharmacology Co-chair of Intercollege Graduate Degree Program in Molecular Toxicology Charles Lang Distinguished Professor of Cellular and Molecular Physiology, and Surgery Co-Chair, Intercollege Graduate Degree Program in Molecular Medicine *Signatures are on file in the Graduate School ii ABSTRACT Cholesterol and iron are essential for a number of cellular processes. Disruption of both cholesterol and iron metabolism have been independently reported to contribute to several diseases including Alzheimer disease (AD) and cancer. AD is a debilitating disease characterized by progressive neuronal loss and memory impairment. Although the underlying cause(s) of AD are not completely understood, iron accumulation and the resultant oxidative stress are well established contributors to the development of AD. Normal iron uptake is mediated by HFE (high iron, also called hemochromatosis protein). H63D and C282Y are two common variants of the HFE protein that are implicated as disease modifying risk factors for AD and several cancers, respectively. The main objective of this thesis was to determine whether a relationship exists between iron and cholesterol metabolism that could be of relevance for understanding the underlying mechanism of diseases such as AD and cancer. This goal was achieved by studying the effect(s) on cholesterol metabolism of two specific variants of HFE (H63D and C282Y) known to affect iron metabolism. The H63D variant of HFE, associated with dysregulation of iron homeostasis, has been implicated as a risk factor for Alzheimer disease (AD). Apolipoprotein epsilon 4 (APOE4), a known risk factor for AD, is associated with disruption of cholesterol metabolism. Recent studies showed that individuals with both the APOE4 allele and the H63D variant of HFE had a much greater risk and earlier onset of AD than individuals carrying either the APOE4 allele or H63D variant of HFE alone. Therefore, the hypothesis that H63D-HFE is associated with development of cognitive impairment by disrupting cholesterol metabolism thereby contributing to increased neurodegeneration, and increased memory deficits was investigated. The effect(s) of H63D-HFE on expression of cholesterol was studied using SH-SY5Y human neuroblastoma cells transfected to stably express either wild type (WT-) or H63D-HFE. The ~50% reduction in cholesterol content in cells expressing H63D-HFE was accompanied by a significant decrease in expression of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCoAR), and a significant increase in expression of cholesterol hydroxylase (CYP46A1). Consistent with in vitro studies, H67D-HFE (homologous to human H63D-HFE) knock-in mice, iii showed a genotype and age dependent decline in brain cholesterol relative to WT-HFE controls and similar changes in expression of proteins regulating cholesterol metabolism. The reduction in cholesterol in brains of H67D-HFE mice was accompanied by a significant decrease in expression of synapse and myelin management proteins, significant increase in caspase-3 expression, and cortical and hippocampal neurodegeneration in the brains of 18 and 24 month old mice. Performance on learning and memory tasks (novel object recognition and Barnes maze) indicated that H67D-HFE mice had poorer cognitive function than WT-HFE mice. Magnetic resonance imaging of 24 month-old mice showed a greater reduction in the volume of brains in H67D-HFE mice. Combined these data indicate that the H63D/H67D variant contributes to the disease process in AD by altering cholesterol metabolism as well as that of iron and that these changes are accompanied by neuronal loss, brain atrophy, and memory impairment which are symptoms of AD. The results also provide a possible explanation for why expression of both APOE4 and H63D-HFE is associated with earlier onset of AD. Disruptions in the maintenance of iron and cholesterol metabolism have also been implicated in several cancers. Therefore, in the second part of this work, the effects of C282Y-HFE on lipid (cholesterol and sphingolipid) metabolism and its possible relevance to cancer phenotype was also studied. Expression of C282Y-HFE altered transcription of a number of enzymes involved in cholesterol and sphingolipid metabolism. More specifically it was associated with significant changes in the expression of genes involved in cholesterol metabolism were consistent with significant elevation in total cholesterol content of C282Y-HFE cells. Of particular interest was the finding that expression of the enzyme sphingosine kinase 1(SphK) and its pro-survival metabolite, sphingosine-1-phosphate (S1P) was elevated. These effects may contribute to the increased risk of colorectal, breast, prostate, ovarian, and brain tumors reported for carriers of C282Y-HFE and explain why it is considered protective against Alzheimer’s disease while H63D-HFE is a risk factor for neurodegenerative diseases. Changes in the gene expression seen for proteins involved in cholesterol metabolism, indicate that increased uptake of cholesterol is the likely cause for the elevation in cellular cholesterol content seen in C282Y-HFE expressing cells. Since simvastatin is an inhibitor of cholesterol synthesis and has been proposed to be beneficial for the treatment of certain iv cancers, its effect on the viability of C282Y-HFE cells was ascertained. A higher concentration of simvastatin was needed to decrease survival of cells expressing C282Y- HFE than WT-HFE. Because of the significant increase of SphK in C282Y cells, the effect of a SphK inhibitor (SKI) on cell survival was monitored. Again, WT-HFE cells were more sensitive to this treatment than C282Y-HFE cells, reflecting the drug resistant phenotype of C282Y-HFE cells. Treatment of cells with both simvastatin and SKI revealed a small effect on survival. Collectively, these studies indicated that C282Y-HFE markedly affected both cholesterol and sphingolipid metabolism and support the possibility that inhibition of both cholesterol synthesis/uptake and as well as synthesis of S1P as a potential therapeutic strategy for treatment of cancer in carriers of C282Y-HFE. Taken together, the studies with both genes variants of HFE provide evidence for the role of HFE in lipid metabolism, in addition to iron management. These data argue for stratification of patients in clinical trials based on HFE genotype to better understand disease mechanism and evaluate therapeutic efficacy of treatments. v TABLE OF CONTENTS List of Figures ……………………………………………………………………………ix List of Tables ………………………………………………………………………….....xi List of Abbreviations…………………………………………………………………….xii Acknowledgments...………………………………………………………………........xvii Chapter 1: Iron, cholesterol, and Alzheimer’s disease……………………………….1 Introduction ……………………………………………………………………………...18 Genetic Risk factors ……………………………………………………………………..20 Mechanisms implicated in AD…………………………………………………………...21 1. Amyloid Hypothesis……………………………………………………………. 22 2. Tau Pathology…………………………………………………………………... 23 3. Mitochondrial Dysfunction …………………………………………………….. 24 4. Oxidative Stress………………………………………………………………… 25 5. Synaptic Faliure ……………………………………………………………….. 26 6. Metal Toxicity………………………………………………………………….. 27 - Iron ………………………………………………………………………… 27 - Iron in AD ………………………………………………………………….. 28 - Iron, HFE, and AD …………………………………………………………. 30 - HFE gene …………………………………………………………………... 31 - Structure of HFE protein……………………………………………………. 32 - Function of HFE ………………………………………………………….. 33 - HFE expression …………………………………………………...………...36 - H63D-HFE and AD………………………………………………………… 36 7. Lipid dyshomeostasis ……………………………………………………………38 Lipid rafts ………………………………………………………………………..38 i) Sphingolipids ………………………………………………………..41 vi -Role of sphingolipids in AD…………………………………… 42 ii) Cholesterol …………………………………………………………..44 - Cholesterol metabolism and function in circulation …………...44 - Cholesterol metabolism in the brain …………………………...45 - Brain vs. plasma cholesterol …………………………………...49 - Role of cholesterol in the brain………………………………... 49 - Cholesterol homeostasis and AD pathology …………………...51 - Cholesterol in aging brain ……………………………………...51 - ApoE functions and isoform-specific effects relevant to AD pathology ………………………………………………………………………………...53 Rationale for thesis ……………………………………………………………………...55 References ………………………………………………………………………………58 Chapter 2: Iron, cholesterol, and Alzheimer’s disease…………………………...…101 Introduction …………………………………………………………………………….101 Experimental Procedures……………………………………………………………… 103 Results ………………………………………………………………………………….111 Discussion ……………………………………………………………………………...121 Figure and legends…………………………………………………………………….. 130 References ……………………………………………………………………………...143 Chapter 3: Effect of HFE variants on sphingolipid
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