Disorders of cholesterol metabolism underlie several human diseases, including heart disease and stroke. Recently, cholesterol metabolism has been recognized to play a major role in the pathogenesis of Alzheimer's disease. My laboratory studies genes that regulate cholesterol metabolism throughout the body, and as such we are at the interface between dementia and cardiovascular research.
ABCA1 is a cholesterol transporter that is widely expressed throughout the body. Outside the central nervous system, ABCA1 functions in the biogenesis of high-density lipoprotein (HDL), where it mediates the efflux of cholesterol and phospholipids to apolipoprotein (apo) A-I. Deficiency of ABCA1 results in lack of circulating HDL and greatly reduced levels of apoA-I. ABCA1 is also expressed in cells of the central nervous system, but its roles in brain lipid metabolism are not yet fully understood. In the brain, glia synthesize the apolipoproteins involved in central nervous system lipid metabolism. We have recently demonstrated that glial ABCA1 is required for cholesterol efflux to apoA-I and plays a key role in facilitating cholesterol efflux to apoE, which is the major apolipoprotein in the brain and a well-established risk factor for Alzheimer's disease. In both astrocytes and microglia, ABCA1 deficiency reduces lipid efflux to exogenous apoE. The impaired ability to efflux lipids in ABCA1-/- glia results in lipid accumulation in both astrocytes and microglia under normal culture conditions. Additionally, apoE secretion is compromised in ABCA1-/- astrocytes and microglia. In vivo, deficiency of ABCA1 results in a 65% decrease in apoE levels in whole brain, and a 75-80% decrease in apoE levels in hippocampus and striatum. Additionally, the effect of ABCA1 on apoE is selective, as apoJ levels are unchanged in brains ABCA1-/- mice. Taken together, these results show that glial ABCA1 is a key influence in apoE metabolism in the brain, and may affect the pathogenesis of Alzheimer's disease. We are currently testing whether deficiency or overexpression of ABCA1 affects Alzheimer's disease in vivo.
Down syndrome (DS) is a very common genetic disorder caused by inheritance of an extra copy of chromosome 21, which results in mental disability, heart defects, hearing loss, obesity, diabetes, cholesterol gallstones, and Alzheimer's disease. DS affects approximately 1 in 1000 births, and is a major concern for older mothers. One of the biggest challenges researchers face is to understand how an extra copy of genes on chromosome 21 causes DS. A significant breakthrough was the completion of the DNA sequence of chromosome 21 and the identification of 225 known or predicted genes. One candidate gene that resides on chromosome 21 is the cholesterol transporter ABCG1. ABCG1 regulates cholesterol trafficking and may therefore affect several problems associated with DS including dyslipidemia, cholesterol gallstone formation, and Alzheimer's disease, all of which are connected to cholesterol metabolism. We hypothesize that inheritance of an extra copy of ABCG1 may explain some of the features observed in patients with DS. To test this hypothesis, we have generated mice that specifically express an extra copy of human ABCG1. Importantly, we have designed these mice to mimic as closely as possible how ABCG1 would be overproduced in DS patients. The overall objective of this project is to characterize the impact of selective ABCG1 overexpression on lipid metabolism of these mice, particularly with respect to Alzheimer's disease, atherosclerosis, and cholesterol gallstone formation.
Karasinska JM, Rinninger F, Lütjohann D, Ruddle P, Franciosi S, Kruit JK, Singaraja RR, Hirsch-Reinshagen V, Fan J, Brunham LR, Bissada N, Ramakrishnan R, Wellington CL, Parks JS, Hayden MR.: Specific loss of brain ABCA1 increases brain cholesterol uptake and influences neuronal structure and function. J Neurosci. 2009 Mar 18;29(11):3579-89.
Parkinson PF, Kannangara TS, Eadie BD, Burgess BL, Wellington CL, Christie BR.: Cognition, learning behaviour and hippocampal synaptic plasticity are not disrupted in mice over-expressing the cholesterol transporter ABCG1. Lipids Health Dis. 2009 Feb 24;8:5.
Burgess B, Naus K, Chan J, Hirsch-Reinshagen V, Tansley G, Matzke L, Chan B, Wilkinson A, Fan J, Donkin J, Balik D, Tanaka T, Ou G, Dyer R, Innis S, McManus B, Lütjohann D, Wellington C.: Overexpression of human ABCG1 does not affect atherosclerosis in fat-fed ApoE-deficient mice. Arterioscler Thromb Vasc Biol. 2008 Oct;28(10):1731-7.
Burgess BL, Parkinson PF, Racke MM, Hirsch-Reinshagen V, Fan J, Wong C, Stukas S, Theroux L, Chan JY, Donkin J, Wilkinson A, Balik D, Christie B, Poirier J, Lütjohann D, Demattos RB, Wellington CL.: ABCG1 influences the brain cholesterol biosynthetic pathway but does not affect amyloid precursor protein or apolipoprotein E metabolism in vivo. J Lipid Res. 2008 Jun;49(6):1254-67.
Hirsch-Reinshagen, V., S. Zhou, B.L. Burgess, L. Bernier, S.A. McIsaac, J.Y. Chan, G.H. Tansley, J.S. Cohn, M.R. Hayden, and C.L. Wellington (2004). Deficiency of ABCA1 impairs apoE metabolism in brain. J Biol Chem 279: 41197-41207.
Selva, D.M., V. Hirsch, S. Zhou, B. Burgess, J. Chan, S. McIsaac, M.R. Hayden, G.L. Hammond, A.W. Vogl, and C.L. Wellington (2004). The ATP-binding cassette transporter ABCA1 mediates lipid efflux from Sertoli cells and contributes to male fertility. J Lipid Res 45: 1040-1050.
Wellington , C.L. (2004). Cholesterol at the crossroads: Alzheimer's disease and lipid metabolism. Clin Genet, 66: 1-16.