Alzheimer's disease (AD) is the most common cause of dementia in the aging population. The importance of lipid alterations in AD pathogenesis has been underscored by the demonstration that the e4 allele of the lipid transporter apolipoprotein E (apoE) is associated with an earlier onset and a higher risk for AD. However, the effects of apoE-mediated alterations of lipid flux in AD pathogenesis are unknown. Sulfatides are specialized integral membrane lipid constituents in the myelin sheath which are essential for neuronal function. We have recently demonstrated that (1) sulfatide content precipitously drops in very mild AD, (2) CMS sulfatide content is modulated by apoE, and (3) the contents of sulfatides {which are associated with apoE in the CMS) and amyloid-beta..1-42 (Abeta42) are highly correlated in human cerebrospinal fluid. Accordingly, we propose that apoE/lipoprotein associated sulfatides specifically facilitate Abeta binding to the apoE particles for normal clearance. However, under pathological conditions where Abeta accumulation occurs, apoEassociated lipoproteins containing sulfatides facilitate Abeta42 aggregation which may form nucleation sites for further Abeta deposition. Furthermore, increased compensatory clearance of Aa/apoE/sulfatide complexes due to an accelerated endocytotic process results in sulfatide depletion. This hypothesis will be tested utilizing three independent models we have developed to study specific interactions, among apoE isoforms, Abeta peptides, and sulfatides. First, we will utilize a defined vesicular model system containing sulfatides as guest in a host phospholipid matrix to examine the kinetics of apoE/Abeta/sulfatide specific interactions by mass spectrometry (sulfatide and Abeta mass), ELISA (apoE content), and NMR spectroscopy (Abeta fibrillogenesis). Second, we will use oligodendrocytes (the cellular source of sulfatides in the CNS) as a cell culture model to identify the importance of sulfatide/apoE/Abeta interactions in modulating Abeta clearance and sulfatide trafficking. Finally, we will utilize transgenic mice to examine the detailed interactions of sulfatides with apoE variants and to verify the salient molecular interactions which modulate sulfatide trafficking and Abeta clearance. Collectively, the results of the proposed studies will explore the specific interactions of su!fatides/apoE/Abeta and address the molecular mechanism(s) leading to sulfatide loss and Abeta aggregation in very early Alzheimer's disease, thereby, providing insight into AD pathogenesis and identifying novel targets for AD treatment.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BDCN-D (90))
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Petanceska, Suzana
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Washington University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
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Cheng, Hua; Zhou, Yunhua; Holtzman, David M et al. (2010) Apolipoprotein E mediates sulfatide depletion in animal models of Alzheimer's disease. Neurobiol Aging 31:1188-96
Han, Xianlin (2010) The pathogenic implication of abnormal interaction between apolipoprotein E isoforms, amyloid-beta peptides, and sulfatides in Alzheimer's disease. Mol Neurobiol 41:97-106
Saadat, Laleh; Dupree, Jeffrey L; Kilkus, John et al. (2010) Absence of oligodendroglial glucosylceramide synthesis does not result in CNS myelin abnormalities or alter the dysmyelinating phenotype of CGT-deficient mice. Glia 58:391-8
Han, Xianlin (2010) Multi-dimensional mass spectrometry-based shotgun lipidomics and the altered lipids at the mild cognitive impairment stage of Alzheimer's disease. Biochim Biophys Acta 1801:774-83
Han, Xianlin; Jiang, Xuntian (2009) A review of lipidomic technologies applicable to sphingolipidomics and their relevant applications. Eur J Lipid Sci Technol 111:39-52
Mancuso, David J; Kotzbauer, Paul; Wozniak, David F et al. (2009) Genetic ablation of calcium-independent phospholipase A2{gamma} leads to alterations in hippocampal cardiolipin content and molecular species distribution, mitochondrial degeneration, autophagy, and cognitive dysfunction. J Biol Chem 284:35632-44
Jiang, Xuntian; Yang, Kui; Han, Xianlin (2009) Direct quantitation of psychosine from alkaline-treated lipid extracts with a semi-synthetic internal standard. J Lipid Res 50:162-72
Cheng, Hua; Mancuso, David J; Jiang, Xuntian et al. (2008) Shotgun lipidomics reveals the temporally dependent, highly diversified cardiolipin profile in the mammalian brain: temporally coordinated postnatal diversification of cardiolipin molecular species with neuronal remodeling. Biochemistry 47:5869-80
Zeng, Youchun; Han, Xianlin (2008) Sulfatides facilitate apolipoprotein E-mediated amyloid-beta peptide clearance through an endocytotic pathway. J Neurochem 106:1275-86
Zeng, Youchun; Cheng, Hua; Jiang, Xuntian et al. (2008) Endosomes and lysosomes play distinct roles in sulfatide-induced neuroblastoma apoptosis: potential mechanisms contributing to abnormal sulfatide metabolism in related neuronal diseases. Biochem J 410:81-92

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