INFLAMMATORY MEDIATORS AND THEIR RELEVANCE TO NEURODEGENERATION

Actually, there is no therapy available for neurodegenerative diseases, and their pathogenesis is, in addition, poorly understood. For example, in Alzheimer’s disease (AD), amyloid-beta (AB), is being regarded as a pivotal factor in the promotion of neuronal damage, although it could not be yet defined as a cause, or rather an effect of neurodegeneration. Nevertheless, accumulation of AB is associated with active inflammation, marked by augmented expression of mediators and their receptors in the brain. Proapoptotic cytokines, such as Tumor Necrosis Factor-a, Fas Ligand, and TRAIL, which bind to the TNF death receptor superfamily, set into motion cellular and molecular events leading to neuronal death. Detrimental effects of AB and other neuronal injuries appear thus, at least in part, mediated by cytokines, and the resulting neurotoxicity implies a complex sequence of events involving multiple signal transduction pathways within the damaged neurons. In fact, an array of molecular mechanisms underlying cytokine-related toxicity in neurodegenerative processes have been identified and characterized in the last decade. These studies strengthened the concept that antagonism of cytokines may be effective in either slowing down or blocking progression of exceeding neuronal death. Interestingly, in models of AB toxicity, immunoneutralization of TRAIL results in significant rescue of apoptotic neurons. In addition, blockade of TRAIL is associated with functional recovery of mice bearing ongoing neurodegeneration. These results support the hypothesis of a key role of neurotoxicity-related inflammation, thus fuelling research of potential pharmacological tools for innovative therapy of neurodegenerative disorders and other diseases of the nervous system.