Oxidative stress appears to be involved in the pathogenesis of Alzheimer's disease, and most likely involves interactions between A? proteins and polyunsaturated fatty acyl (PUFA) chains. Therefore, we are proposing to (1) determine whether the expression of A? proteins increases the rate of oxidative PUFA metabolism and degradation in brain, and whether the rates differ in disease-prone and disease-resistant regions of brain;(2) test whether A? proteins increase protein modification by lipid oxidation products in general, and whether A? proteins are modified in vivo by the lipid oxidation products that accelerate their aggregation into amyloid fibrils;and (3) test whether specific dietary and pharmacological interventions alter the production of toxic PUFA degradation products in disease-prone brain regions, or the fate of PUFA degradation products in these regions. We will make use of radiolabeled PUFA chains, which will be injected into transgenic mouse models of Alzheimer's disease, as well as quantitative and sequencing mass spectrometry.

Public Health Relevance

The pathogenesis of Alzheimer's disease may involve oxidative stress and specific interactions between A? proteins and polyunsaturated fatty acyl chains in the brain. The proposed research involves the biosynthesis of polyunsaturated fatty acyl radiotracers that will be used as in vivo probes of oxidative stress in animal models of Alzheimer's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS074178-03
Application #
8479445
Study Section
Biochemistry and Biophysics of Membranes Study Section (BBM)
Program Officer
Corriveau, Roderick A
Project Start
2011-09-01
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$337,750
Indirect Cost
$126,656
Name
University of Pennsylvania
Department
Pharmacology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Yeung, Priscilla S-W; Eskici, Gozde; Axelsen, Paul H (2013) Infrared spectroscopy of proteins in reverse micelles. Biochim Biophys Acta 1828:2314-8