Abstract

The proposed research is a biophysical study of the process by which lipid membranes induce aggregation and pathologically mis-folded secondary structure in amyloid beta (Ab) proteins.
It aims to define mechanistic links between two major themes in the pathogenesis of Alzheimer's disease: amyloid fibril formation and oxidative damage. It is hypothesized that these processes are linked through protein-lipid interactions, and we have developed novel instrumentation for characterizing these interactions. We are specifically proposing to (1) Determine the secondary structure of membrane-associated Af3 protein, (2) Correlate Ab folding and accumulation to membrane composition and source, and (3) Define potential consequences of Ab-induced oxidative membrane damage. This research addresses basic pathological mechanisms of Alzheimer's Disease by addressing the complex interrelationships between Ab fibril formation, lipid membranes, and oxidative damage in both synthetic membranes and membranes derived from pathologically afflicted human brain tissue. In this way, the concept of membrane-mediated amyloidogenesis will be developed on a molecular and pathologically-relevant level.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG020238-01A1
Application #
6544358
Study Section
Special Emphasis Panel (ZRG1-MDCN-2 (01))
Program Officer
Snyder, Stephen D
Project Start
2002-07-01
Project End
2007-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
1
Fiscal Year
2002
Total Cost
$306,139
Indirect Cost

  Institution

Name
University of Pennsylvania
Department
Pharmacology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104

  Publications

Grasso, Giuseppe; Axelsen, Paul H (2017) Effects of covalent modification by 4-hydroxy-2-nonenal on the noncovalent oligomerization of ubiquitin. J Mass Spectrom 52:36-42
Murphy, Robert C; Axelsen, Paul H (2011) Mass spectrometric analysis of long-chain lipids. Mass Spectrom Rev 30:579-99
Axelsen, Paul H; Murphy, Robert C (2010) Quantitative analysis of phospholipids containing arachidonate and docosahexaenoate chains in microdissected regions of mouse brain. J Lipid Res 51:660-71
Komatsu, Hiroaki; Liu, Liu; Murray, Ian V J et al. (2007) A mechanistic link between oxidative stress and membrane mediated amyloidogenesis revealed by infrared spectroscopy. Biochim Biophys Acta 1768:1913-22
Aygun-Sunar, Semra; Mandaci, Sevnur; Koch, Hans-George et al. (2006) Ornithine lipid is required for optimal steady-state amounts of c-type cytochromes in Rhodobacter capsulatus. Mol Microbiol 61:418-35
Murray, Ian V J; Sindoni, Michael E; Axelsen, Paul H (2005) Promotion of oxidative lipid membrane damage by amyloid beta proteins. Biochemistry 44:12606-13
Paul, Cynthia; Axelsen, Paul H (2005) beta Sheet structure in amyloid beta fibrils and vibrational dipolar coupling. J Am Chem Soc 127:5754-5
Schneeweis, Lumelle A; Koppaka, Vishwanath; Lund-Katz, Sissel et al. (2005) Structural analysis of lipoprotein E particles. Biochemistry 44:12525-34
Greenbaum, Eric A; Graves, Charles L; Mishizen-Eberz, Amanda J et al. (2005) The E46K mutation in alpha-synuclein increases amyloid fibril formation. J Biol Chem 280:7800-7
Paul, Cynthia; Wang, Jianping; Wimley, William C et al. (2004) Vibrational coupling, isotopic editing, and beta-sheet structure in a membrane-bound polypeptide. J Am Chem Soc 126:5843-50

Showing the most recent 10 out of 11 publications