ABSTRACT
Several reports have indicated that synaptic, physiological, and behavioral abnormalities precede Aβ plaque deposition in AD transgenic mice, supporting the possibility that Aβ plaques may not be the critical pathogenic matter. However, potential roles for pre-amyloid protofibrils and intraneuronally accumulated Aβ may prove to be important for the pathogenic process.6,7 There are two major C-terminal variants of Aβ. Aβ1-40 is the major species secreted from cultured cells and is found in cerebrospinal fluid, whereas Aβ1-42 is the major component of amyloid deposits in brain with AD.8 Increases in Aβ1-42, which is more susceptible to aggregation and formation of fibrils, have also been detected in transgenic mice and cells expressing familial AD (FAD) mutations of both APP and presenilins.9 These results suggest a link between this variant of Aβ and AD pathogenesis in that the polymerization of Aβ into protease-resistant fibrils is a significant step in the pathogenesis of AD.9,10 The neurotoxicity exerted by aggregated Aβ can be mediated by several mechanisms, such as the generation of reactive oxygen species (ROS), dysregulation of calcium homeostasis, inflammatory response, and activation of some signaling pathways.11-14
15.2.1 Aβ AND OXIDATIVE STRESS The AD brain is subjected to increased oxidative stress resulting from free-radical damage.15 The sites in the AD brain where neurodegeneration occurs and oxidative stress exists are reported to be associated with increased Aβ deposits.16 Although the mechanism of Aβ-associated free-radical formation is not fully understood, Aβ is believed to contact or insert into the neuronal and glial membrane bilayer and then generate oxygen-dependent free radicals that cause lipid peroxidation and protein oxidation.17 It has been shown that Aβ causes H2O2 accumulation in cultured hippocampal neurons18 and in neuroblastoma cultures.19 Electron paramagnetic resonance analysis of gerbil synaptosomes using a 12-nitroxyl stearate spin probe demonstrated that Aβ induced lipid peroxidation.20 Increased oxidative modifications of proteins such as advanced glycation end-products have been found to increase DNA oxidation, and increased peroxidation of membrane lipids has been found in the brains of patients with AD upon autopsy.21 Furthermore, Koppaka and Axelsen22 demonstrated that phospholipid membranes with oxidative damage promoted β-sheet formation by Aβ, suggesting the possible role of lipid peroxidation in the pathogenesis of AD. In addition, it has been shown recently that oligomeric Aβ, not monomeric or fibrillar Aβ, promoted the release of lipid, cholesterol, phospholipids, and mono-sialoganglioside from cultured neurons and astrocytes in a dose-and time-dependent manner. These findings indicate that oligomeric Aβ promotes lipid release from the neuronal membrane, which may lead to the disruption of neuronal lipid homeostasis and the loss of neuronal function23. Loss of membrane integrity resulting from Aβ-induced free-radical damage may lead
to cellular dysfunction such as inhibition of ion-motive ATPase, imbalance of calcium homeostasis, inhibition of Na-dependent glutamate uptake of glial cells, disturbance of signaling pathways, activation of nuclear transcription factors, and apoptotic pathways. Aβ-associated free-radical generation might be strongly influenced by the aggregation state of the peptides.24 Neuronal death may be the ultimate consequence of these cellular dysfunctions.17
