ments given to patients significantly delayed the time to institutionalization (Sano et al., 1997). Antioxidants also enhance cognition in rat models, and antioxidant application or diet supplementation can improve spatial memory (Joseph et al., 1999; Socci et al., 1995). Currently, an Alzheimer's Disease Cooperative Study using a randomized, double-blind, placebo-controlled trial is evaluating the safety and efficacy of 2,000 IU of Vitamin E to delay the clinical progression of elderly populations from mild cognitive impairment to Alzheimer's disease. Thus, there is strong rationale for the further evaluation of this intervention in an aging model in which the time interval between cognitive assessment and biochemical/neuroanatomical study can be tightly controlled. We need to evaluate dietary interventions using both short-term and long-term clinical trials.
The presence of a mechanism to hold degeneration in check may provide an explanation for one of the seeming controversies in the Alzheimer's disease literature. As we have described, TUNEL labeling provides evidence for active apoptosis in a large subset of neurons in the Alzheimer's-affected brain. However, many more Alzheimer's-affected neurons exhibit evidence for DNA damage in the absence of morphological changes, indicative of terminal apoptosis, for example, the formation of nuclear apoptotic bodies. In classical apoptosis, cells die within hours or days of the initial insult. If TUNEL labeling in the Alzheimer's-affected brain reflected the true initiation of classical apoptosis, then it follows that most TUNEL-positive neurons would die in a few days. However, in many mild cases of Alzheimer's disease (MMSE above 16), over 50 percent of the neurons exhibit TUNEL labeling. Thus, most neurons should have degenerated within a few days if apoptosis is actively in progress in these cells, a prediction that is inconsistent with the progression of neuronal loss in Alzheimer's disease. In addition, most TUNEL-positive neurons do not exhibit morphological markers of apoptosis, such as nuclear apoptotic bodies or other key molecular factors (Su et al., 1994; Lucassen et al., 1997) This apparent inconsistency has led some to the conclusion that neurons in the Alzheimer's-affected brain die primarily by necrosis (Stadelmann et al., 1998).
On the other hand, it is possible that neurons have developed a series of counteractive measures to repair damage and delay death, in other words, a kind of molecular counterattack in order to minimize unnecessary cell loss. This concept of an apoptosis checkpoint cascade may help to understand an apparent puzzle in the neuronal apoptosis literature: the prolonged presence of indices of DNA damage and apoptotic regulatory protein expression may be a result of a counteractive strategy that neurons mobilize to hold apoptosis