Raf inhibition protects cortical cells against β-amyloid toxicity

Alzheimer's disease (AD) is the main cause of dementia in the elderly. The discovery of new targets of therapeutic intervention is fundamental to the development of new drugs against AD pathology. Upregulation of cRaf-1 has been found post-mortem in the brains of AD patients. cRaf-1 is a cytosolic protein kinase that regulates neuronal survival and senescence. In this study, we investigated cRaf-1 in the brains of aged APPswe mice presenting AD-like pathology and whether Raf inhibitors protected cultured cortical cells against amyloid beta toxicity (A beta). We found a dysregulation of cRaf-1 in the cortex of APPswe mice, which showed a 147% increase in the active form phosphorylated at serine 338 and a 40% decrease in the levels of the inactive form of cRaf-1, phospho-cRaf-1 [Ser259]. Furthermore, treatment of primary cortical neurons with the cRaf-1 inhibitors, GW5074 or ZM336372, and the nuclear factor kappa B (NF kappa B) inhibitor SN50, protected cortical neurons against A beta toxicity. Since Raf stimulates NF kappa B, we studied the effect of Raf inhibition on its activation by studying changes in NF kappa B phosphorylation at serine 276. Our results suggest that Raf inhibition with GW5074 is neuroprotective against A beta toxicity through a mechanism that involves NF kappa B inhibition. (C) 2008 Elsevier Ireland Ltd. All rights reserved.