FIGURE B-3 The immune responses in the brain are a critical part of homeostasis but when chronically activated may contribute to the evolution of brain pathology. Neurons and glia express receptors and ligands in the TNF superfamily (A). In the presence of inflammatory stimuli such as Aβ, oxidation and select cytokines would be predicted to be up-regulated (B) and thus would make cells at risk for activating pro-apoptotic mechanisms similar to that reported in the aging immune system.

one lipid peroxidation product, 4-hydroxynonenal (HNE), is elevated in the brains and cerebrospinal fluids of cases of Alzheimer's disease (Lovell et al., 1997; Markesbery and Lovell, 1998), is toxic in vitro and in vivo, and impairs visuospatial memory in rats at physiological levels (Bruce-Keller et al., 1998). Isoprostane, a chemically stable peroxidation product of arachidonic acid, increases as well and is used as a marker for the extent of lipid peroxidation in vivo. In particular, Praticao et al. (1998) demonstrated that isoprostanes were elevated in the brains and cerebrospinal fluids of patients with Alzheimer's disease.

Oxidative stress can also lead to the misprocessing of APP to form amyloidogenic products. Several in vitro experiments suggest that energy-related metabolic stress leads to reduced levels of secreted APP mediated by β-secretase and in fact, may lead to increased production of amyloidogenic fragments (Gabuzda et al., 1994; Gasparini et al., 1997; Multhaup et al., 1997). Oxidative stress increases the production of both APP and β-amyloid (Frederikse et al., 1996). β-amyloid itself can lead to the generation of reactive oxygen species (ROS), superoxide radicals, hydroxynonenal (HNE), and membrane lipid peroxidation (Mark et al., 1997; Behl et al., 1992; Pereira et



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