Basic FGF attenuates amyloid β-peptide-induced oxidative stress, mitochondrial dysfunction, and impairment of Na +/K +-ATPase activity in hippocampal neurons

Abstract

Basic fibroblast growth factor (bFGF) exhibits trophic activity for many populations of neurons in the brain, and can protect those neurons against excitotoxic, metabolic and oxidative insults. In Alzheimer's disease (AD), amyloid β-peptide (A β) fibrils accumulate in plaques which are associated with degenerating neurons. A β can be neurotoxic by a mechanism that appears to involve induction of oxidative stress and disruption of calcium homeostasis. Plaques in AD brain contain high levels of bFGF suggesting a possible modulatory role for bFGF in the neurodegenerative process. We now report that bFGF can protect cultured hippocampal neurons against A β25-35 toxicity by a mechanism that involves suppression of reactive oxygen species (ROS) accumulation and maintenance of Na +/K +-ATPase activity. A β25-35 induced lipid peroxidation, accumulation of H 2O 2, mitochondrial ROS accumulation, and a decrease in mitochondrial transmembrane potential; each of these effects of A β25-35 was abrogated in cultures pre-treated with bFGF. Na +/K +-ATPase activity was significantly reduced following exposure to A β25-35 in control cultures, but not in cultures pre-treated with bFGF. bFGF did not protect neurons from death induced by ouabain (a specific inhibitor of the Na +/K +-ATPase) or 4-hydroxynonenal (an aldehydic product of lipid peroxidation) consistent with a site of action of bFGF prior to induction of oxidative stress and impairment of ion-motive ATPases. By suppressing accumulation of oxyradicals, bFGF may slow A β-induced neurodegenerative cascades.