Raf inhibition protects cortical cells against beta-amyloid toxicity

Neuroscience Letters
Valentina EcheverriaBruce A Citron

Abstract

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 (Abeta). 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 (NFkappaB) inhibitor SN50, protected cortical neurons against Abeta toxicity. Since Raf stimulates NFkappaB, we studied the effect of Raf inhibition on its activation by studying changes in NFkappaB phosphorylation at serine 276. Our results suggest that Raf inhibition with GW5074 is neuroprotective against Abeta toxicit...Continue Reading

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Citations

Mar 3, 2012·Neurological Sciences : Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology·Amteshwar Singh Jaggi, Nirmal Singh
Jan 5, 2012·PloS One·Alberto FerlinCarlo Foresta
Feb 14, 2012·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Amteshwar Singh Jaggi, Nirmal Singh

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