Blas Frangione

An assessment of the antioxidant and the antiamyloidogenic properties of melatonin: implications for Alzheimer's disease

Summary. This review summarizes recent advancements in our understanding of the potential role of the amyloid β protein in Alzheimers disease. It also discusses the significance of amyloid β in initiating the generation of partially reduced oxygen species and points out their role in damaging essential macromolecules in the CNS which leads to neuronal dysfunction and loss. Recently acquired experimental data links these destructive oxidative processes with some neurodegenerative aspects of Alzheimers disease. The experimental findings related to the free radical scavenging and antioxidative properties of melatonin are tabulated and its efficacy and the likely mechanisms involved in its ability to reduce neuronal damage mediated by oxygen-based reac-tive species in experimental models of Alzheimers disease are summarized. Besides the direct scavenging properties and indirect antioxidant actions of melatonin, its ability to protect neurons probably also stems from its antiamyloidogenic properties. Melatonin is also unique because of the ease with which it passes through the blood-brain barrier.

Potent neuroprotective properties against the Alzheimer β-amyloid by an endogenous melatonin-related indole structure, indole-3-propionic acid

Widespread cerebral deposition of a 40–43-amino acid peptide called the amyloid β-protein (Aβ) in the form of amyloid fibrils is one of the most prominent neuropathologic features of Alzheimer’s disease. Numerous studies suggest that Aβ is toxic to neurons by free radical-mediated mechanisms. We have previously reported that melatonin prevents oxidative stress and death of neurons exposed to Aβ. In the process of screening indole compounds for neuroprotection against Aβ, potent neuroprotective properties were uncovered for an endogenous related species, indole-3-propionic acid (IPA). This compound has previously been identified in the plasma and cerebrospinal fluid of humans, but its functions are not known. IPA completely protected primary neurons and neuroblastoma cells against oxidative damage and death caused by exposure to Aβ, by inhibition of superoxide dismutase, or by treatment with hydrogen peroxide. In kinetic competition experiments using free radical-trapping agents, the capacity of IPA to scavenge hydroxyl radicals exceeded that of melatonin, an indoleamine considered to be the most potent naturally occurring scavenger of free radicals. In contrast with other antioxidants, IPA was not converted to reactive intermediates with pro-oxidant activity. These findings may have therapeutic applications in a broad range of clinical situations.

A novel Polish presenilin-1 mutation (P117L) is associated with familial Alzheimer's disease and leads to death as early as the age of 28 years.

THE majority of early-onset familial Alzheimers disease (FAD) is associated with mutations in the presenilin-1 (PS1) gene. We describe a novel Polish PS1 mutation of Pro117Leu, associated with the earliest average age of onset and death so far reported in a PS-linked, FAD kindred. Human kidney 293 and mouse neuroblastoma N2a cells were stably transfected with wild-type and PS1 P117L. There was a significant increase in the amyloid β42/40 ratio in the N2a P117L PS1 transfected cells compared with N2a transfected with wild-type PS1. What role PS has in the pathogenesis of AD remains to be determined, however, the severity of the clinical picture associated with this PS1 mutation stresses the importance of presenilin.