Beta Amyloid and Oxidative Stress in Alzheimer's Disease: Core B Amyloid

Alzheimer’s disease (AD) is one of the major health problems in this country and affects over 4.5 million persons. The key to the disease is understanding the pathogenesis of neuron degeneration in specific brain regions so that treatment and prevention can be based on solid data. This application is a resubmission of a competitive renewal of the program project, “Beta-Amyloid and Oxidative Stress in AD” (P01 AG05119-20) by the Sanders-Brown Center on Aging at the University of Kentucky (UK). Abundant evidence indicates that free radical mediated oxidative damage in the brain is prominent in AD, especially in the earliest detectable clinical phase of AD — mild cognitive impairment (MCI). The major hypothesis of this application is that betaamyloid peptide (Af3) is one of the pivotal mechanisms in oxidative stress/damage to neurons in AD. The proposal consists of three cores including 1) an Administrative Core that provides supervision, fiscal management, biostatistical support and database management, clinical and neuropathological data, and brain specimens from the UK AD Center, 2) a unique Beta-Amyloid Core that will provide the Aj3 index (total A1314o and AB142, A13 solubility, oligomeric and fibrillar A13 quantitation and plaque quantitation) from human subjects and transgenic mice and also will provide toxic assembled A13 and non-toxic scrambled A13 for cell culture experiments, and 3) an Animal Core that will supply APP/PSi knock-in mutant mice and WT mice, and primary rodent cortical neuron cultures for projects. Each project uses short postmortem brain specimens from longitudinally followed preclinical AD (PCAD), MCI, late AD, normal controls and frontotemporal dementia (as a disease control) subjects, APP/PSi transgenic mice and cell cultures, and each has a therapeutic component and excellent preliminary data to support their hypotheses. Project 1 examines the hypothesis that brain RNA oxidation is an early event in AD and is mediated, at least in part, by Af3 and that the RNA oxidation impairs protein synthesis and contributes to neuron dysfunction. Project 2 examines the hypothesis that A13-mediated oxidative modifications of and subsequent dysfunction of Pini are fundamental to the genesis of specific pathological features in AD. Project 3 will examine the hypothesis that elevations in RAGE-ligand interactions occur in AD, with soluble RAGE modulating A13 assembly and toxicity. Project 4 examines the hypothesis that sustained activation of NADPH oxidase by toxic forms of Aj3 triggers a cascade linking increased ROS to altered redox-based signaling and neurotoxic oxidative damage. This well integrated program project will move the field of A13 and oxidative stress in AD forward and gain insights into mechanisms of neuron degeneration so that successful interventions can be developed to treat or prevent the most dehumanizing disorder to affect humans.