Iron Enhances the Neurotoxicity of Amyloid β

Brain microbleeds often occur in Alzheimer's disease patients. Our previous studies have demonstrated that iron contributes to brain injury following intracerebral hemorrhage. This study investigated the effect of iron on amyloid beta (A beta)-mediated brain injury. There are two parts to this study. In the first part, rats received an intracaudate injection of saline, iron, A beta 25-35, or iron + A beta 25-35. In the second part, rats received intracaudate injection of iron + A beta and were treated with saline or cystamine, an inhibitor of transglutaminase. Rats were killed after 24 h for brain edema measurement. DNA damage, neuronal death, and tissue-type transglutaminase (tTG) expression were also examined. We found that brain water content in the ipsilateral caudate was higher (p<0.05) in rats injected with iron + A beta than with iron, A beta, or saline. Combined iron + A beta injection also resulted in more severe DNA damage (both single- and double-strand, p<0.01) and more Fluoro-Jade C staining (p<0.05). Expression of tTG increased markedly in the iron + A beta group (p<0.05), and treatment with a tTG inhibitor reduced brain edema (p<0.05) and reduced degenerating neurons (124 +/- 25 vs. 249 +/- 50/mm(2) in vehicle-treated group, p<0.05). These results suggest that increased brain iron from microbleeds may exaggerate brain A beta toxicity and that tTG is involved in the enhanced toxicity.