BASIC FGF ATTENUATES AMYLOID BETA-PEPTIDE-INDUCED OXIDATIVE STRESS, MITOCHONDRIAL DYSFUNCTION, AND IMPAIRMENT OF NA+ K+-ATPASE ACTIVITY IN HIPPOCAMPAL-NEURONS/

Basic fibroblast growth factor (bFGF) exhibits trophic activity for ma ny populations of neurons in the brain, and can protect those neurons against excitotoxic, metabolic and oxidative insults. In Alzheimer's d isease (AD), amyloid beta-peptide (A beta) fibrils accumulate in plaqu es which are associated with degenerating neurons. A beta can be neuro toxic by a mechanism that appears to involve induction of oxidative st ress and disruption of calcium homeostasis. Plaques in AD brain contai n high levels of bFGF suggesting a possible modulatory role for bFGF i n the neurodegenerative process. We now report that bFGF can protect c ultured hippocampal neurons against A beta 25-35 toxicity by a mechani sm that involves suppression of reactive oxygen species (ROS) accumula tion and maintenance of Na+/K+-ATPase activity. A beta 25-35 induced l ipid peroxidation, accumulation of H2O2, mitochondrial ROS accumulatio n, and a decrease in mitochondrial transmembrane potential; each of th ese effects of A beta 25-35 was abrogated in cultures pre-treated with bFGF. Na+/K+-ATPase activity was significantly reduced following expo sure to A beta 25-35 in control cultures, but not in cultures pre-trea ted with bFGF. bFGF did not protect neurons from death induced by ouab ain (a specific inhibitor of the Na+/K+-ATPase) or 4-hydroxynonenal (a n aldehydic product of lipid peroxidation) consistent with a site of a ction of bFGF prior to induction of oxidative stress and impairment of ion-motive ATPases. By suppressing accumulation of oxyradicals, bFGF may slow A beta-induced neurodegenerative cascades.