This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Amyloidogenic processing of APP results in the generation of Abeta peptide fragments that are involved in the etiology of Alzheimers disease (AD). The complete elucidation of the mechanisms that regulate APP processing has not been realized. We undertook a screen of ATP-binding cassette transporters expressed in the brain for their effects on APP metabolism. Our current results suggest that the ATP-binding cassette transporter (ABCA2) is a regulator of APP processing and Abeta production. Genetic evidence by single nucleotide polymorphism (SNP) mapping identified a single synonymous mutation in ABCA2 that is significantly associated with early-onset AD. We determined that ABCA2 overexpression in HEK293 cells bearing the APP Swedish mutation (APPsw) increased cellular APP holoprotein levels and Abeta secretion. Using microarray analysis of gene expression profiles in HEK293 cells stably transfected with ABCA2, we detected elevated levels of a number of genes associated with AD. Although these findings suggest that ABCA2 may be a key regulator of APP metabolism, ABCA2 regulation of APP processing was not examined in either neuronal cells or in transgenic mice expressing mutant forms of APP. The recent production of an ABCA2 knockout mouse will permit the unequivocal determination of the function of the ABCA2 transporter in regulating APP processing and Abeta production in vivo. We do not know the physiological significance of ABCA2 in regulating APP processing and Abeta production. A central hypothesis of this COBRE project is that ABCA2 functions in neuronal cells to regulate APP processing and Abeta production and thereby serves a critical role in maintaining homeostasis between amyloidogenic and non-amyloidogenic pathways of APP metabolism. We shall undertake experiments to determine if ABCA2 protein levels modulate APP processing and the consequences for neuropathology and learning performance in transgenic mouse models of the disease.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory Grants (P20)
Project #
2P20RR017677-06
Application #
7610450
Study Section
Special Emphasis Panel (ZRR1-RI-5 (01))
Project Start
2007-08-01
Project End
2008-06-30
Budget Start
2007-08-01
Budget End
2008-06-30
Support Year
6
Fiscal Year
2007
Total Cost
$171,762
Indirect Cost
Name
Medical University of South Carolina
Department
Biochemistry
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Zunke, Friederike; Moise, Alexandra C; Belur, Nandkishore R et al. (2018) Reversible Conformational Conversion of ?-Synuclein into Toxic Assemblies by Glucosylceramide. Neuron 97:92-107.e10
Vila├ža, Rita; Barros, Ivo; Matmati, Nabil et al. (2018) The ceramide activated protein phosphatase Sit4 impairs sphingolipid dynamics, mitochondrial function and lifespan in a yeast model of Niemann-Pick type C1. Biochim Biophys Acta Mol Basis Dis 1864:79-88
Chen, Wei; Wang, Bo; Gruber, Jordon D et al. (2018) Acyl Carrier Protein 3 Is Involved in Oxidative Stress Response in Pseudomonas aeruginosa. Front Microbiol 9:2244
Fekry, Baharan; Jeffries, Kristen A; Esmaeilniakooshkghazi, Amin et al. (2018) C16-ceramide is a natural regulatory ligand of p53 in cellular stress response. Nat Commun 9:4149
Jin, Junfei; Lu, Zhongyang; Li, Yanchun et al. (2018) LPS and palmitate synergistically stimulate sphingosine kinase 1 and increase sphingosine 1 phosphate in RAW264.7 macrophages. J Leukoc Biol 104:843-853
Snider, Justin M; Snider, Ashley J; Obeid, Lina M et al. (2018) Probing de novo sphingolipid metabolism in mammalian cells utilizing mass spectrometry. J Lipid Res 59:1046-1057
Zhang, Ning; Valentine, Joseph M; Zhou, You et al. (2017) Sustained NF?B inhibition improves insulin sensitivity but is detrimental to muscle health. Aging Cell 16:847-858
Pulkoski-Gross, Michael J; Uys, Joachim D; Orr-Gandy, K Alexa et al. (2017) Novel sphingosine kinase-1 inhibitor, LCL351, reduces immune responses in murine DSS-induced colitis. Prostaglandins Other Lipid Mediat 130:47-56
Alexaki, Aikaterini; Clarke, Benjamin A; Gavrilova, Oksana et al. (2017) De Novo Sphingolipid Biosynthesis Is Required for Adipocyte Survival and Metabolic Homeostasis. J Biol Chem 292:3929-3939
Hao, Limin; Ben-David, Oshrit; Babb, Suzann M et al. (2017) Clozapine Modulates Glucosylceramide, Clears Aggregated Proteins, and Enhances ATG8/LC3 in Caenorhabditis elegans. Neuropsychopharmacology 42:951-962

Showing the most recent 10 out of 196 publications