Investigators continue to tease out the ways in which oxidative stress, which occurs as a result of over-production of free radicals, may play a role in neuronal damage and death. For example, one research team from Case Western Reserve University in Cleveland, Ohio, has attempted to distinguish the particular cell types in the brain that are most vulnerable to oxidative stress (Nunomura et al., 1999). They found that most of the oxidative damage to DNA and RNA in vulnerable neurons of AD involves RNA, not DNA. The several classes of RNA molecules, which are chemically similar to DNA, play essential roles in carrying genetic information from DNA in the nucleus to the outer portion of the cell, where the information serves as a blueprint for the manufacture of specific proteins. RNA also plays a critical role in the actual synthesis of the proteins. Oxidatively damaged RNA may interfere with these processes, and this may cause a malfunctioning protein to be made (one that has either gained a toxic function or lost a normal function). In turn, this could be one cause of the neuronal death that characterizes AD.
Other recent studies, conducted by scientists at the Sanders-Brown Center on Aging and the NIA-supported Alzheimer’s Disease Research Center, have built on previous work detailing the direct evidence for free radical damage to neurons in AD. In one of these studies, scientists confirmed that certain types of free radicals, called 4-hydroxynonenal (HNE), which are toxic to neurons, are increased in several regions of the brain that have the most AD damage (Markesbery and Lovell, 1998). This study, in conjunction with cell culture studies and previous studies showing HNE elevation in cerebrospinal fluid of AD patients, suggests that HNE may also be important in the development of neuron damage in AD.
In a review of many studies on oxidative stress, the same team of investigators present evidence that the oxidative process damages brain fats, carbohydrates, proteins, and DNA, and also summarize the evidence for inflammatory processes in the brains of AD patients (Markesbery and Carney, 1999). They suggest that it is these two processes, working in concert, that contribute to the death of brain neurons and the consequent decline in mental function seen in AD patients.
National Institutes of Health
National Institute on Aging
1999 PROGRESS REPORT ON ALZHEIMER’S DISEASE