I am grateful to my scientific colleagues, who have found this paper of interest. Our laboratory first formulated the hypothesis that amyloid b -peptide (1-42) [Ab (1-42)], a toxic, 42-amino acid peptide found in Alzheimer’s disease brain, is associated with free radical oxidative stress and that the oxidative stress induced by the peptide was neurotoxic. This paper summarizes what was known about the peptide up until the publication of this paper in 2000. A framework to explain much of the extant literature on AD was formulated and supported by many studies from our laboratory and those of others. From this paper, I think scientists and physicians were excited to learn about this framework in order to gain insight into potential mechanisms of neurodegeneration in AD brain.

Yes. This paper summarizes a new paradigm for the neurotoxicity caused by Ab (1-42). Namely, free radical oxidative stress associated with the peptide, and manifested as lipid peroxidation, protein oxidation, reactive oxygen species formation, and inhibited by free radical antioxidants, causes neurotoxicity. This new paradigm accounts for two main observations in AD: (1) the growing evidence that Ab (1-42) is the ultimate cause of AD pathogenesis; and (2) the oxidative stress in AD brain that has been reported from many laboratories, including ours. Additionally, our research has shown that the single methionine residue of Ab (1-42) is critical to the oxidative stress and neurotoxic properties of this peptide. This helps provide a potential mechanism by which the effects of Ab (1-42) are manifested.

  Could you summarize the significance of your paper in layman’s terms?

The principal significance of this paper is that a new way of understanding the death of brain cells in Alzheimer’s disease was developed based on the free radical (highly reactive molecules) damage to neurons associated with amyloid b -peptide. This peptide accumulates in Alzheimer’s disease brain, and many researchers now believe that this peptide is central to the mechanisms by which the memory loss, other symptoms, and pathology of this dementing disorder arise. This new way of understanding the importance of amyloid b -peptide as an initiator of free radical damage to brain cells also suggests possible therapeutic strategies for Alzheimer’s disease: namely, brain-accessible antioxidants may be able to modulate the damage associated with the peptide. In the laboratory, free radical antioxidants are highly effective in blocking the harmful effects of free radicals associated with amyloid b -peptide.

From the time I was a graduate student at Duke University, I have always applied the principles of physical and biological chemistry to neurological problems. At the University of Kentucky, in collaboration with Prof. William Markesbery, our laboratory has been able to describe numerous oxidative stress alterations in the Alzheimer’s disease brain employing a wide variety of biophysical and biochemical methods. Most recently, our laboratory has used the emerging techniques of proteomics to identify which specific proteins are oxidatively modified in the Alzheimer’s disease brain, from which new insights into potential mechanisms for neurodegeneration have been developed. For the exciting work on amyloid b -peptide-associated free radical oxidative stress, I became involved in 1993 by asking this question: How is it that the literature of Alzheimer’s disease is full of reports of changes in structure and function of numerous proteins, enzymes, lipids, etc.? How could one disease have so many things wrong? Then, it occurred to me, "what if there were a free radical present, and wherever the free radical was formed in the neuron, it would react with whatever was near it? That entity would be modified by the free radical or its sequelae, resulting in altered function."

I learned that amyloid b -peptide was the central component of one of the pathological hallmarks of Alzheimer’s disease, so I obtained a sample of this peptide and determined that free radicals and oxidative stress were associated with the peptide. The rest, as is often said, is history. Since that first observation, published in 1994, a large number of refereed papers have appeared from our laboratory and those of others to show that Ab causes lipid peroxidation, protein oxidation, free radical formation, and numerous alterations in the structure and function of neurons. All these effects in neurons or brain membrane systems are inhibited by free radical scavengers. We hypothesize that small aggregates of Ab , perhaps as small as dimers, tetramers, or hexamers, are the toxic species of the peptide and free radical oxidative stress is the damaging mechanism associated with the peptide that leads to neuronal death in Alzheimer’s disease brain. Consistent with this hypothesis, we recently showed that oxidative stress occurred in vivo in a living animal that expressed human Ab (1-42) prior to deposition of the peptide but coincident with the onset of the phenotypic expression (paralysis) in the C. elegans.