Neuronal oxidative stress precedes amyloid-β deposition in Down syndrome

The predictable chronological sequence of pathological events in Down syndrome (DS) provides the opportunity to rigorously investigate the relationship between oxidative stress and amyloid-beta (A beta) deposition. In this study, we,report a marked accumulation of oxidized nucleic acid, 8-hydroxyguanosine (8OHG), and oxidized protein, nitrotyrosine, in the cytoplasm of cerebral neurons in DS with the levels of nucleic acid and protein oxidation paralleling each other. Relative density measurements of neuronal 8OHG immunoreactivity showed that there was a significant increase (p < 0.02) in DS (n = 22, ages 0.3-65 yr) compared with age-matched controls (n = 10, ages 0.3-64 yr). As a function of age, 8OHG immunoreactivity increased significantly in the teens and twenties (p < 0.04), while AP burden only increased after age 30 (p < 0.0001). In 9 cases of DS bearing A<beta> deposition, the extent of deposits of A beta ending at amino acid 42 (A beta 42) was actually associated with a decrease in relative 8OHG (r = -0.79, p < 0.015) while A<beta>40 was not. These findings suggest that in brains of patients with DS, increased levels of oxidative damage occur prior to the onset of A beta deposition.