al., 1999; McDonald et al., 1997). There is also evidence that β-amyloid can itself be oxidized resulting in enhanced aggregation (Dyrks et al., 1992).
The accumulation of amyloidogenic fragments, in turn, accelerates existing molecular cascades associated with oxidative stress. β-amyloid also promotes cell dysfunction by increasing the expression levels of bax, decreasing levels of bcl-2 (Paradis et al., 1996), and, in many systems, activating caspases. Thus, decreases in bcl-2 from oxidative stress and Aβ insults can leave cells particularly vulnerable to oxidative stress (Hochman et al., 1998). Finally, activation of caspases cleaves APP, producing additional β-amyloid fragments (Gervais et al., 1999; Barnes et al., 1998; LeBlanc et al., 1999). These are exciting leads, as they suggest alternative mechanisms for the production of β-amyloid.
Oxidative stress may lead to an initial increase in cellular compensatory mechanisms mediated by the expression of pro-and anti-apoptotic proteins. One family of proteins, the bcl-2 family, serves as an intracellular checkpoint and determines whether or not a cell engages in an apoptotic program (Oltvai et al., 1993). Bcl-2 can be inactivated by the formation of heterodimers with a second highly homologous protein, bax. Bax promotes apoptotic cell death (Oltvai et al., 1993; Reed, 1994). Thus, the balance between levels of bcl-2 and bax can serve as an indicator of cellular state. Ultimately, we hypothesize, this compensatory mechanism is inadequate and eventually leads to decreased bcl-2 levels with a corresponding increase in bax, shifting the system to a neurodegenerative status. Exposing neuronal or endothelial cells to oxidative stress decreases levels of bcl-2 and increases the expression levels of bax (Longoni et al., 1999; Maroto and Perez-Polo, 1997).
Thus, we can hypothesize that oxidative stress causes a cascade of events in which there are multiple positive feedback loops that amplify the cascade. For example: (1) oxidative damage within mitochondria leads to further free radical production, (2) increased oxidation leads to additional Aβ, which in turn generates additional APP, (3) Aβ and accumulating oxidative damage activates caspases, which in turn cleaves APP and generates additional Aβ and oxidative damage, and (4) progressive oxidative damage and Aβ decreases bcl-2, leaving neurons more vulnerable to oxidative damage and other insults. Common to each of these events is oxidative damage. Thus, an antioxidant intervention should, in principle, suppress the progression of brain pathology at one or more steps in the cascade. This is consistent with a vast and somewhat unappreciated literature on the efficacy of antioxidants in the aging process.
There is a growing body of literature indicating that administration of antioxidants to aged animals and individuals can have dramatic effects on