Aluminum-induced neurodegeneration involves differential regulation of proinflammatory cytokine and neurotrophin gene expression.
Toxicologist 2003 Mar; 72(S-1):23
The etiology of human neurodegenerative diseases including Alzheimer's disease (AD) is exceedingly complex and our understanding of the mechanisms involved is far from complete. The experimental neurotoxicology of aluminum has been shown to recapitulate virtually every pathophysiological feature of AD and therefore represents a useful model to study the mechanisms involved in neurodegeneration. The present study investigated the effects of aluminum maltolate (Al-malt) on the delicate balance that exists between pro-inflammatory cytokines and neurotrophins using primary brain rotation-mediated aggregate cultures. Aggregates were treated with Al-malt (5-150 microM) on day 15 in vitro for 72 h. Cell death increased in a time- and concentration-dependent manner reaching significance in aggregates treated with 150 microM Al-malt in 48 h and 50 microM by 72 h. Analysis of gene expression at 72 h revealed a concentration-dependent increase in tumor necrosis factor alpha and macrophage inflammatory protein-1alpha suggestive of a state of inflammation. In contrast, a dramatic concentration-dependent decrease in the expression of nerve growth factor (NGF) and brain derived neurotrophic factor was observed. In fact, NGF expression could not be detected in aggregates treated with 50 and 150 microM Al-malt. These changes in gene expression correlated with a decrease in aggregate size and an increase in neurodegeneration as indicated by Fluoro-Jade B staining. The results indicated a differential regulation of pro-inflammatory cytokines and neurotrophins in brain tissue following treatment with Al-malt. Such findings provide insight into the possible involvement of deregulation of the cytokine/neurotrophin balance in the etiology of neurodegeneration.
Aluminum-compounds; Metals; Metal-poisoning; Metal-compounds; Cellular-reactions; Cell-damage; In-vitro-studies; Neurotoxic-effects; Neurotoxicology; Neurotoxicity
The Toxicologist. Society of Toxicology 42nd Annual Meeting and ToxExpo, Cutting-Edge Science, Networking, New Perspectives, March 9-13, 2003, Salt Lake City, Utah