It is generally postulated that the progressive neurodegeneration occurring in sporadic Alzheimer's disease (AD) is a result, at least in part, of the neurotoxic properties of the amyloid beta protein (Abeta). Deposits of this protein are widespread within the brains of individuals affected with AD. The neurotoxic effects of Abeta are mediated by free-radicals and depend on the predominant secondary structure of the protein and/or in its polymerization into fibrils. In addition, the mentioned structural characteristics of Abeta determine the rate of amyloid formation, resistance to proteolysis and tissue clearance. Since these features are also considered key to amyloid accumulation, the mechanisms and factors implicated in fibrillogenesis and neurotoxicity are among the most important issues in AD. We recently found that melatonin, a pineal hormone with a proposed role in the aging process, has remarkable cytoprotective properties against Abeta-induced neurotoxicity. While investigating the mechanisms of action of melatonin, we found that in addition to protecting cells against oxidative stress and death, this substance markedly inhibited the progressive formation of beta-sheet structures of Abeta as well as its polymerization into fibrils. Thus, the hormone exhibits anti- amyloidogenic properties that may be synergistic with its powerful antioxidant activity. In addition, melatonin shows many advantages over conventional antioxidants. The lack of toxicity and the ease and rapidity with which this molecule enters the central nervous system makes it an ideal candidate for experimental testing. In contract with conventional antioxidants, melatonin has a proposed role in the aging process. Its rhythmic secretion is known to be altered in aging and more profoundly in populations with dementia. This grant proposes to use a transgenic mouse model to demonstrate whether the novel in vitro effects can be corroborated in vivo. Moreover, the neuroprotective effects of melatonin will be compared with another conventional antioxidant (PBN), which is structurally unrelated to melatonin and is known to protect neurons against Abeta toxicity but exhibits no anti-amyloidogenic properties in vitro. These studies are necessary for the design of human trials and to further characterize mechanistic aspects (i.e., oxidative stress) of the disease pathogenesis.
