Alzheimer's Disease (AD) is a neurodegenerative brain disorder that afflicts more than 4.5 million elderly Americans. The long-term objective of this competitive renewal application continues to be to investigate mechanisms that might initiate and propagate the neurodegenerative processes that occur in the AD brain. All neurons that die in AD are either located entirely in the cortex and hippocampus/amygdala complex or project from various subcortical cell bodies and connect to the latter brain regions. This remarkable anatomic selectivity of neuronal damage involving many neurotransmitter systems suggests that the neurodegenerative processes have defined starting points and progress only along specific connected neuronal pathways. This project is aimed at exploring the hypothesis that AD is initiated as a result of aberrant oxidation reactions of 5-hydroxytryptamine (5-HT) and norepinephrine (NE) in the axon terminals of long serotonergic and noradrenergic neurons, respectively, at the points where they innervate blood capillaries in the cortex and hippocampus. Leakage of erythrocytes from these microvessels, known to be abnormally permeable in AD, is proposed to provide a localized source of low molecular weight iron which reacts with H2O2 and/or molecular oxygen to generate oxygen radicals that initiate the oxidation of 5-HT and NE giving a number of toxin aberrant metabolites. These toxins are proposed to potentiate their own synthesis by various mechanisms that generate elevated intraneuronal fluxes of O2-., H2O2 and HO. and evoke a retrograde degeneration of serotonergic and noradrenergic neurons. Evidence will be provided to suggest that the 5-HT and NE uptake mechanisms might play key roles in potentiating synthesis of toxic metabolites so that they are formed at highest concentrations at axon terminals along the length of serotonergic and noradrenergic fibers. Thus, these axon terminals may serve as point sources of toxins that evoke the degeneration of parent serotonergic and noradrenergic neurons and connected glutamatergic, cholinergic, dopaminergic and other neurons by mechanisms that include: (a) interactions with various calcium channel receptors leading to disruption of intraneuronal Ca2+ homeostasis; (b) elevated release of glutamate with resultant NMDA receptor-mediated excitotoxicity; (c) uncoupling of mitochondrial oxidative phosphorylation; and, (d) intraneuronal redox cycling reactions with resultant cytotoxic oxygen radical formation. Such mechanisms are proposed to account for the anatomically-selective neurodegeneration that occurs in the AD brain. Specific aims are: (a) to elucidate the in vitro oxygen radical-mediated oxidation chemistry of 5-HT and NE and to identify key intermediates and products of these reactions, i.e., putative aberrant oxidative metabolites (PAOMs); and, (2) to employ in vitro and in vivo neuropharmacological/ neurotoxicological methods to identify PAOMs that possess neurodegenerative/ neurobiological activities that might contribute to neuronal damage in AD.
NIH ExPorter
NIH ExPorter