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.
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.
|Furman, Ran; Murray, Ian V J; Schall, Hayley E et al. (2016) Amyloid Plaque-Associated Oxidative Degradation of Uniformly Radiolabeled Arachidonic Acid. ACS Chem Neurosci 7:367-77|
|Klinger, Alexandra L; Kiselar, Janna; Ilchenko, Serguei et al. (2014) A synchrotron-based hydroxyl radical footprinting analysis of amyloid fibrils and prefibrillar intermediates with residue-specific resolution. Biochemistry 53:7724-34|
|Yeung, Priscilla S-W; Eskici, GÃ¶zde; Axelsen, Paul H (2013) Infrared spectroscopy of proteins in reverse micelles. Biochim Biophys Acta 1828:2314-8|