Alzheimer's disease (AD) is characterized by senile plaques comprised of aggregated amyloid beta proteins (Ab). Neuronal degeneration and evidence of DMA,protein and lipid oxidation are associated with these plaques comprised of Ab. The ability of Ab to interact with lipids, reduce Cu(ll) and produce hydrogen peroxide suggests a role for Ab in lipid oxidation. Indeed, this laboratory has evidence that Ab accelerates oxidative damage of phospholipids. These oxidatively damaged phospholipids, on the other hand, promote the misfolding of Ab and its membrane association. Since oxidatively damaged phospholipids accelerate misfolding of Ab and Ab in turn can promote oxidative damage, there is the possibility of pathological positive-feedback in which oxidatively damaged lipids promote amyloid formation, and amyloid promotes further oxidative lipid damage. The GENERAL AIM of this proposal is to determine if such a positive feedback process occurs in vivo, and whether this positive feedback plays a role in..the. pathogenesis of Alzheimer's disease. The CENTRAL HYPOTHESIS of this proposal is that the interaction of Ab with a lipid membrane produces at least one reactive lipid oxidation product that can chemically modify Ab and promote misfolding of Ab. """"""""""""""""'?;i- The SPECIFIC AIMS are to: 1. characterize Ab that have been chemically modified by lipid oxidation products 2. determine whether Ab increase the production of oxidation products that modify Ab 3. demonstrate the presence of modified Ab in human brain tissue These specific aims will be addressed with an array of modern instrumentation for proteomics and lipidomics, including ESI/LC/MS/MS, GC/MS, and MALDI/TOFrTOF mass spectrometry. Although this is not a proposal to do proteomics or lipidomics per SB, spjnepf the methodology and instrumentation developed within these fields is ideally suited to achieving the stated aims. ... ?. ; -. ' )? ?.i ?? ,
(in lay terms). Alzheimer's disease is characterized by devastating memory loss and it affects a large proportion of the aging population. In this disease there is accumulation of misfolded amyloid proteins and chemically damaged lipids in the brain. We propose to test whether amyloid proteins damage lipids and damaged lipids cause more amyloid protein to misfold. If a cycle like this occurs, it may play an important role in causing Alzheimer's disease, and.be a valuable therapeutic target.
| Ellis, Grace; Fang, Erica; Maheshwari, Mukesh et al. (2010) Lipid oxidation and modification of amyloid-ýý (Aýý) in vitro and in vivo. J Alzheimers Dis 22:593-607 |
| Maheshwari, Mukesh; Roberts, Jessica K; Desutter, Brent et al. (2010) Hydralazine modifies A? fibril formation and prevents modification by lipids in vitro. Biochemistry 49:10371-80 |
| Murray, Ian V J; Liu, Liu; Komatsu, Hiroaki et al. (2007) Membrane-mediated amyloidogenesis and the promotion of oxidative lipid damage by amyloid beta proteins. J Biol Chem 282:9335-45 |
