ABCG1, Down Syndrome and Alzheimer's disease
Cholesterol is increasingly recognized to play a role in Alzheimer's Disease (AD), suggesting that genes that regulate cholesterol may affect the process of AD. Down Syndrome (DS) is a genetic disease caused by inheritance of an extra copy of chromosome 21. A prominent feature of DS is the inevitable development of AD by the mid-late 30s, decades earlier than the general population. Notably, chromosome 21 contains a gene known as ABCG1 that is highly expressed in brain and that is involved in cholesterol metabolism. Dr. Wellington shows that ABCG1 increases the production of Abeta peptides, which are the toxic species that accumulate in AD and DS brains. This result suggests that ABCG1 may connect cholesterol with the acceleration of AD in DS. In this proposal, Dr. Wellington will evaluate whether ABCG1 accelerates AD pathology in a mouse model and study exactly how ABCG1 works in a cell culture model system. She will also initiate studies of ABCG1 in human and mouse brain tissue as a first step in translating the results into applications for human health. This research will determine whether eventual therapies for AD may be based on ABCG1, which will be applicable for both the general and DS populations.
Burgess, B.L., Parkinson, P.F., Bryan, M.T., Su, Y., Hirsch-Reinshagen, V., Fan, J., Wong, C., Therous, L., Chan, J.Y., Donkin, J., Wilkinson, A., Christie, B., Poirier, J., Lutjohann, D., deMattos, R.B., and Wellington, C.L. (2007) ABCG1 influences brain cholesterol synthesis but not affect amyloid precursor protein or apolipoprotein E metabolism in vivo. J Lipid Res. 2008 Jun;49(6):1254-67. Epub 2008 Feb 26.
Parkinson, P.F., Kannangara, T.S., Eadie, B.D., Burgess, B.L., Wellington, C.L., Christie, B.R. (2009) Cognition, learning behavior and hippocampal synaptic plasticity are not disrupted in mice over-expressing the cholesterol transporter ABCG1. Lipids Health Dis, 24: 8-15.
Burgess, B.L., Naus, K.E., Chan, J.Y., Hirsch-Reinshagen, V.U, Matzke, L., Chan, B., Wilkinson, A., Fan, J., Balik, D., Tanaka, T., Ou, G., Dyer, R., Innis, S., McManus, B., Lutjohann, D., and Wellington, C.L. (2008) Overexpression of human ABCG1 does not affect atherosclerosis in fat-fed apoE-deficient mice. Arterioscler Thromb Vasc Biol. 2008 Oct;28(10):1731-7. Epub 2008 Jul 3.
First published on: June 10, 2008
Last modified on: September 2, 2010