Presented by Biochemical Pharmacology Discussion Group
Cholesterol and Alzheimer's Disease: Exploring the Pathways
Posted November 30, 2006
Over the past decade, as cell biologists and biochemists have investigated the complex pathogenesis of Alzheimer’s disease (AD) with new tools in neurochemistry, the metabolic pathways of cholesterol in the brain have generated fruitful and promising research, produced new ideas, and helped to advance old hypotheses. Epidemiologic observations support a relationship between lipid metabolism in the brain and AD, but much work remains to elucidate it and harvest any clinical yield.
The cholesterol-related molecules and their various AD-related behaviors and pathways were on prominent display at a meeting at the Academy on May 23, 2006, when four leading scientists presented results from their ongoing research. They offered hard-won insights into lipid metabolism in the microstructures of the brain, the continuing and unfolding significance of apolipoprotein E (apoE) and amyloid precursor protein (APP, the parent to toxic Aβ), together with more recent interest in the cholesterol-reducing statins and ABCA1, an ABC transporter molecule.
General information is available here concerning the relationship between Alzheimer's, cholesterol, and statins.
Alzheimer Research Forum
Try this query for news about research on Alzheimer's disease nd cholesterol.
National Library of Medicine
Check this site for up-to-the-minute news on research and clinical trials related to Alzheimer's disease, plus excellent links for caregivers, coping, and alternative therapies.
NIH Senior Health
The official Alzheimer's pages of the National Institutes of Health; it is mostly patient-oriented.
Perry, G., J. Avila, J. Kinoshita & M. A. Smith, Eds. 2006. Alzheimer's Disease: A Century of Scientific and Clinical Research. Ios Press, Amsterdam, The Netherlands.
Overview: Cholesterol and Alzheimer's Disease
Wellington, C.L. 2004. Cholesterol at the crossroads: Alzheimer's disease and lipid metabolism. Clin. Genet. 66: 1-16.
Wolozin, B. 2002. Cholesterol and Alzheimer's disease. Biochem. Soc. Trans. 30: 525-529.
Cholesterol, Statins, and Alzheimer's Disease
Jick, H., G. L. Zornberg, S. S. Jick, et al. 2000. Statins and the risk of dementia. Lancet 356: 1627-1631.
Li, G., J. B. Shofer, W. A. Kukull, et al. 2005. Serum cholesterol and risk of Alzheimer disease: a community-based cohort study. Neurology 65: 1045-1050.
Rea, T. D., J. C. Breitner, B. M. Psaty, et al. 2005. Statin use and the risk of incident dementia: the Cardiovascular Health Study. Arch. Neurol. 62: 1047-1051.
Shepherd, J., G. J. Blauw, M. B. Murphy, et al. 2002. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 360: 1623-1630.
Wolozin, B. 2004. Cholesterol, statins and dementia. Curr. Opin. Lipidol. 15: 667-672.
Wolozin, B. 2001. A fluid connection: cholesterol and Aβ. Proc. Natl. Acad. Sci. USA 98: 5371-5373.
Wolozin, B, J. Brown III, C. Theisler, S. Silberman. 2004. The cellular biochemistry of cholesterol and statins: insights into the pathophysiology and therapy of Alzheimer's disease. CNS Drug Rev. 10: 127-146.
Wolozin, B., W. Kellman, P. Rousseau, et al. 2000. Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch. Neurol. 57: 1439-1443.
Yaffe, K., E. Barrett-Connor, F. Lin & D. Grady. 2002. Serum lipoprotein levels, statin use, and cognitive function in older women. Arch. Neurol. 59: 378-382.
Zandi, P. P., D. L. Sparks, A. S. Khachaturian, et al. 2005. Do statins reduce risk of incident dementia and Alzheimer disease? The Cache County Study. Arch. Gen. Psychiatry 62: 217-224.
Processing of APP in Cholesterol-Rich Membrane Microdomains
Vetrivel, K. S., H. Cheng, S. H. Kim, et al. 2005. Spatial segregation of γ-secretase and substrates in distinct membrane domains. J. Biol. Chem. 280: 25892-25900.
Vetrivel, K. S., H. Cheng, T. Sakurai, et al. 2004. Association of γ-secretase complex with lipid raft microdomains in post-Golgi and endosomes membranes. J. Biol. Chem. 279: 44945-44954.
Vetrivel, K. S. & G. Thinakaran. 2006. Amyloidogenic processing of β-amyloid precursor protein in intracellular compartments. Neurology 66: S69-73.
Understanding the Relationship Between ApoE Structure and Disease
Morrow, J. A., D. M. Hatters, B. Lu, et al. 2002. Apolipoprotein E4 forms a molten globule. A potential basis for its association with disease. J. Biol. Chem. 277: 50380–50385.
Raffai, R. L. & K. H. Weisgraber. 2002. Hypomorphic apolipoprotein E mice. A new model of conditional gene repair to examine apolipoprotein E-mediated metabolism. J. Biol. Chem. 277: 11064-11068.
ABCA1, apoE, and Amyloid Deposition in Alzheimer's Disease
Hirsch-Reinshagen, V., L. F. Maia, B. L. Burgess, et al. 2005. The absence of ABCA1 decreases soluble ApoE levels but does not diminish amyloid deposition in two murine models of Alzheimer disease. J. Biol. Chem. 280: 43243-43256. Epub 2005 Oct 5.
Hirsch-Reinshagen, V., S. Zhou, B. L. Burgess, et al. 2004. Deficiency of ABCA1 impairs apolipoprotein E metabolism in brain. J. Biol. Chem. 279: 41197-41207.
Katzov, H., K. Chalmers, J. Palmgren, et al. 2004. Genetic variants of ABCA1 modify Alzheimer disease risk and quantitative traits related to beta-amyloid metabolism. Hum. Mutat. 23: 358-367.
Kölsch, H., D. Lütjohann, F. Jessen, et al. 2006. Polymorphism in ABCA1 influences CSF 24S-hydroxycholesterol levels but is not a major risk factor of Alzheimer's disease. Int. J. Mol. Med. 17: 791-794.
Li, Y., K. Tacey, L. Doil, et al. 2004. Association of ABCA1 with late-onset Alzheimer's disease is not observed in a case-control study. Neurosci. Lett. 366: 268-271.
Shibata, N., T. Kawarai, J. H. Lee, et al. 2006. Association studies of cholesterol metabolism genes (CH25H, ABCA1 and CH24H) in Alzheimer's disease. Neurosci. Lett. 391: 142-146.
Wollmer, M. A., J. R. Streffer, D. Lutjohann, et al. 2003. ABCA1 modulates CSF cholesterol levels and influences the age at onset of Alzheimer's disease. Neurobiol. Aging 24: 421-426.
Benjamin Wolozin, MD, PhD
Benjamin Wolozin studies the pathophysiology of Alzheimer's and Parkinson's disease. In particular, since discovering the ameliorative effects of statins on Alzheimer's in 2000, he has been investigating the link between cholesterol and AD. His work on Parkinson's focuses on the interaction between genes and environmental factors in causing the disease.
Wolozin earned his MD and PhD degrees at the Albert Einstein College of Medicine as part of the Medical Scientist Training Program, and completed postdoctoral fellowships at Mt. Sinai Medical Center and the National Institute of Mental Health. He later joined Loyola University Medical Center and since 2004 has been a professor of pharmacology in the Department of Pharmacology and Experimental Therapeutics at Boston University Medical Campus.
Gopal Thinakaran, PhD
Gopal Thinakaran is an associate professor in the Department of Neurobiology, Pharmacology, and Physiology at the University of Chicago. He also serves on the university's committees on cell physiology, molecular medicine, and neurobiology. In addition to his work on the links between cholesterol and Alzheimer's disease, he also studies the biology of neuronal stress response in an effort to characterize the early events that lead to the etiopathogenesis of AD and other neurodegenerative disorders.
Thinakaran completed his PhD in molecular biology and genetics at the University of Guelph in Ontario, Canada.
Karl H. Weisgraber, PhD
Karl Weisgraber is a senior investigator at the Gladstone Institute of Neurological Disease, and professor of pathology at the University of California, San Francisco. He studies the relationship of the structure and function of apolipoprotein E in cardiovascular and Alzheimer's disease.
Cheryl L. Wellington, PhD
Cheryl Wellington is an assistant professor in the Department of Pathology & Laboratory Medicine at the University of British Columbia Child & Family Research Institute. Her focus is on cholesterol metabolism, particularly in the central nervous system, and she has worked to identify the connection between the cholesterol transport molecule ABCA1 in glial cells and the pathogenesis of Alzheimer's disease. In current work she is testing whether deficiency or overexpression of ABCA1 affects Alzheimer's disease in vivo. She is also investigating the role that the cholesterol transporter ABCG1 may play in causing the inheritance of an extra copy of chromosome 21 in individuals with Down syndrome.
Weillington completed her PhD at the University of British Columbia.
John Gailbraith Simmons
John Gailbraith Simmons is a nonfiction author, novelist, and journalist who writes about the history of science and medicine for popular and professional audiences. He is the author of The Scientific 100, which profiles one hundred of the most influential scientists in history, and Doctors and Discoveries: Lives that Created Today's Medicine.