The overall goals of this grant application are to study potential mechanisms associated with regulation of neuronal transbilayer and lateral cholesterol domains and how cholesterol domains interact with calcium homeostasis in neuronal membranes of different age groups of mice. We have recently shown in synaptic plasma membranes (SPM) of young C57BL mice, that the two membrane leaflets are asymmetric in their fluidity and cholesterol distribution. Membrane cholesterol was also found to be located in exchangeable and non-exchangeable pools and membrane cholesterol domains could be altered by hydrolysis of sphingomyelin that also altered intracellular calcium. Preliminary data from out laboratory showed that the asymmetry of fluidity between the two SPM leaflets observed in 6 month old animals was significantly reduced in SPM of 28 month old animals and that the exofacial leaflet was more affected as compared to the cytofacial leaflet. Previous studies on membrane lipid structure in different age groups of animals have examined changes in the average fluidity of the membrane lipid structure, whereas other studies have not observed age differences. We propose that increasing age is associated with marked changes in membrane lipid structure but that such changes are occurring in specific lipid domains and changes in lipid domains contribute to modification of calcium homeostasis that has been previously shown to differ with increasing age. The proposed experiments will focus on SPM and synaptosomes of 4, 16, and 28 month old C57BL/NNia mice.
The specific aims of this application are to: 1) determine transbilayer distribution of cholesterol in the SPM exofacial and cytofacial leaflets; 2) examine cholesterol lateral domains in SPM; 3) phospholipid distribution in SPM exofacial and cytofacial leaflets; 4) involvement of sphingomyelin in regulation of cholesterol domains; 5) brain sterol carrier proteins and regulation of cholesterol domains; and 6) cholesterol domains and presynaptic calcium. It is our working hypothesis that aging impairs the capacity of the membrane to regulate cholesterol domains and such changes in cholesterol domains modify neuronal calcium.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG011056-03
Application #
2052269
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1993-09-30
Project End
1997-08-31
Budget Start
1995-09-01
Budget End
1996-08-31
Support Year
3
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Pharmacology
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Igbavboa, Urule; Hamilton, Jillonne; Kim, Hee-Yong et al. (2002) A new role for apolipoprotein E: modulating transport of polyunsaturated phospholipid molecular species in synaptic plasma membranes. J Neurochem 80:255-61
Wood, W Gibson; Schroeder, Friedhelm; Igbavboa, Urule et al. (2002) Brain membrane cholesterol domains, aging and amyloid beta-peptides. Neurobiol Aging 23:685-94
Avdulov, N A; Chochina, S V; Igbavboa, U et al. (1999) Lipid binding to sterol carrier protein-2 is inhibited by ethanol. Biochim Biophys Acta 1437:37-45
Mason, R P; Jacob, R F; Walter, M F et al. (1999) Distribution and fluidizing action of soluble and aggregated amyloid beta-peptide in rat synaptic plasma membranes. J Biol Chem 274:18801-7
Pu, L; Igbavboa, U; Wood, W G et al. (1999) Expression of fatty acid binding proteins is altered in aged mouse brain. Mol Cell Biochem 198:69-78
Wood, W G; Schroeder, F; Avdulov, N A et al. (1999) Recent advances in brain cholesterol dynamics: transport, domains, and Alzheimer's disease. Lipids 34:225-34
Pu, L; Annan, R S; Carr, S A et al. (1999) Isolation and identification of a mouse brain protein recognized by antisera to heart fatty acid-binding protein. Lipids 34:363-73
Pu, L; Foxworth, W B; Kier, A B et al. (1998) Isolation and characterization of 26- and 30-kDa rat liver proteins immunoreactive to anti-sterol carrier protein-2 antibodies. Protein Expr Purif 13:337-48
Simonyi, A; Xia, J; Igbavboa, U et al. (1998) Age differences in the expression of metabotropic glutamate receptor 1 and inositol 1,4,5-trisphosphate receptor in mouse cerebellum. Neurosci Lett 244:29-32
Igbavboa, U; Avdulov, N A; Chochina, S V et al. (1997) Transbilayer distribution of cholesterol is modified in brain synaptic plasma membranes of knockout mice deficient in the low-density lipoprotein receptor, apolipoprotein E, or both proteins. J Neurochem 69:1661-7

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