We will use a newly developed high throughput sensitive, quantitative proteomic approach to detect key proteins and signaling pathways that are oxidatively damaged during aging and Alzheimer's disease (AD). We will accurately identify the initial targets of age- and ABeta-mediated oxidative stress and their association with neuropathology. This addresses several key elements of this RFA as both normal brain aging and AD are associated with free radical-mediated damage and a loss of synaptic function. which may be a primary cause of cognitive impairments. Many age-related oxidative stress-mediated processes are attenuated by Caloric Restriction (CR). We have recently demonstarted that CR also reduces ABeta deposition and glial activation in the bigenic mutated presenilin & amyloid precursor protein (PS1+APP) mouse models of AD. In addition, using liquid chromatography-mass spectrmetry proteomic methodology, we discovered that certain proteins associated with learning and memory (e.g., NMDA/AMPA receptor, fyn, CaMKII) are oxidatively damaged in the PS1+APP mouse. Therefore, we propose to identify key proteins and signaling pathways involved in free radical mediated syanptic dysfuntion during normal aging and AD using our sensitive and accurate proteomic approach in the PS1+APP mouse. Since CR attenuates many age-related oxidative stress mediated processes, we will determine which proteins and pathways are protected by this dietary intervention. 1: We will use quantitative proteomics to determine the initial targets of free radicals in PSI+APP transgenic and nontransgenic mice to establish the functional links between neuropathological changes and oxidative modification of key synaptic signaling proteins. 2: We will identify the phosphorylation alterations in cell signaling pathways that mediate synaptic dysfunction during aging and Abeta-mediated pathology. 3: We will perform statistical validation of protein identifications from database searches and we will use bioinformatcis to integrate our proteomic data into signaling pathways to identify the underlying mechanisms involved in synaptic dysfunction in the PS1+APP mouse model.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG025323-02
Application #
6950253
Study Section
Special Emphasis Panel (ZAG1-ZIJ-5 (O1))
Program Officer
Snyder, Stephen D
Project Start
2004-09-30
Project End
2006-06-30
Budget Start
2005-09-01
Budget End
2006-06-30
Support Year
2
Fiscal Year
2005
Total Cost
$325,167
Indirect Cost
Name
University of Southern California
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Thomas, Stefani N; Yang, Austin J (2017) Mass Spectrometry Analysis of Lysine Posttranslational Modifications of Tau Protein from Alzheimer's Disease Brain. Methods Mol Biol 1523:161-177
Clark, David J; Fondrie, William E; Liao, Zhongping et al. (2015) Redefining the Breast Cancer Exosome Proteome by Tandem Mass Tag Quantitative Proteomics and Multivariate Cluster Analysis. Anal Chem 87:10462-9
Lima, Florence; Ding, Dacheng; Goetz, Wilfried et al. (2014) High LET (56)Fe ion irradiation induces tissue-specific changes in DNA methylation in the mouse. Environ Mol Mutagen 55:266-77
Liao, Zhongping; Thomas, Stefani N; Wan, Yunhu et al. (2013) An Internal Standard-Assisted Synthesis and Degradation Proteomic Approach Reveals the Potential Linkage between VPS4B Depletion and Activation of Fatty Acid ?-Oxidation in Breast Cancer Cells. Int J Proteomics 2013:291415
Thomas, Stefani N; Liao, Zhongping; Clark, David et al. (2013) Exosomal Proteome Profiling: A Potential Multi-Marker Cellular Phenotyping Tool to Characterize Hypoxia-Induced Radiation Resistance in Breast Cancer. Proteomes 1:87-108
Peng, Zhimin; Liao, Zhongping; Dziegielewska, Barbara et al. (2012) Phosphorylation of serine 51 regulates the interaction of human DNA ligase I with replication factor C and its participation in DNA replication and repair. J Biol Chem 287:36711-9
Liao, Zhongping; Wan, Yunhu; Thomas, Stefani N et al. (2012) IsoQuant: a software tool for stable isotope labeling by amino acids in cell culture-based mass spectrometry quantitation. Anal Chem 84:4535-43
Lin, H Helen; Li, Xu; Chen, Jo-Lin et al. (2012) Identification of an AAA ATPase VPS4B-dependent pathway that modulates epidermal growth factor receptor abundance and signaling during hypoxia. Mol Cell Biol 32:1124-38
Thomas, Stefani N; Funk, Kristen E; Wan, Yunhu et al. (2012) Dual modification of Alzheimer's disease PHF-tau protein by lysine methylation and ubiquitylation: a mass spectrometry approach. Acta Neuropathol 123:105-17
Thomas, Stefani N; Waters, Katrina M; Morgan, William F et al. (2012) Quantitative proteomic analysis of mitochondrial proteins reveals prosurvival mechanisms in the perpetuation of radiation-induced genomic instability. Free Radic Biol Med 53:618-28

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