Oxidative Balance in Alzheimer's Disease: Relationship to APOE, Braak Tangle Stage, and the Concentrations of Soluble and Insoluble Amyloid-beta

Oxidative damage is greater in brain tissue from patients with Alzheimer's disease (AD) than age-matched controls. The timing of this damage in relation to other pathogenic processes in AD remains unclear. We have examined the relationship of lipid peroxidation (thiobarbituric acid-reactive substances; TBARS) and antioxidant capacity (Trolox-equivalent) to APOE status, Braak tangle stage, amyloid-beta (A beta) plaque load, and the concentration of soluble and insoluble forms of A beta, post-synaptic and dendritic spine proteins PSD95 and drebrin, beta-secretase and A beta-degrading enzymes neprilysin (NEP), insulin-degrading enzyme (IDE), and angiotensin-converting enzyme (ACE), in frontal, temporal, and parietal cortex from AD and control brains. Antioxidant capacity was significantly elevated in AD and directly related to disease severity as indicated by Braak tangle stage and the amount of insoluble A beta. APOE epsilon 4 was associated with increased antioxidant capacity in AD but not controls. In contrast, apart from a reduction in TBARS in Braak stages III-IV in frontal cortex, this measure of oxidative damage did not change significantly with any indicator of disease severity. It was, however, higher in APOE epsilon 4-positive than epsilon 4-negative AD patients and correlated with beta-secretase activity. Neither antioxidant capacity nor oxidative damage was related to the level of PSD95 or drebin or the activity of NEP, IDE, or ACE. Antioxidant capacity in AD is closely related to the level of insoluble A beta and increases with pathological progression of the disease. Increased beta-secretase activity associated with oxidative stress is likely to contribute to the accumulation of A beta and this, in turn, to induce antioxidant capacity.