Antioxidants in the treatment of Alzheimer's disease: Breakthrough potential of indole-3propionic acid

Much evidence points to the central role of amyloid-beta protein (Abeta-induced toxicity in the pathogenesis of Alzheimer's disease (AD). Treatment strategies that target Abeta include: (a) decreasing its production; (b) increasing its clearance; (c) inhibiting its toxic fibrillar aggregation; (d) preventing oxidative damage and cytotoxicity. A promising new drug candidate to target Abeta is indole-3-propionic acid, a naturally occurring potent scavenger of damaging hydroxyl radicals and an effective inhibitor of Abeta fibrillogenesis.(1) Numerous in vitro and animal studies indicate that indole-3-propionic acid inhibits aggregation of Abeta, protects human cortical neurons from the toxicity of Abeta, and importantly, protects the brain from oxidative damage produced by a variety of powerful, oxidative, stress-inducing neurotoxins. Moreover, indole-3-propionic acid belongs to a unique class of molecules that have no pro-oxidant activity. This is in contrast to other well-known antioxidants, including vitamin C, vitamin E, glutathione, and other indole compounds, all of whose metabolites have pro-oxidant activity. Indole-3-propionic acid, a deamidation product of tryptophan, is a naturally occurring molecule produced by bacteria in the gastrointestinal tract. It is normally present in blood and cerebrospinal fluid and, importantly, has been tested at pharmacological concentrations in laboratory animals without demonstrating evidence of toxicity. In this chapter, we review the importance of oxidative stress in AD, and compare known properties of indole-3-propionic with other antioxidants that have been tested or are under development for the treatment of AD. We also summarize the status of indole-3-propionic acid's development as a pharmaceutical in the treatment of AD.