β Amyloid, present in senile plaques, has been related largely to neuronal loss in the brain of patients with Alzheimer's disease. However, how neurons respond to β amyloid insults is still poorly understood. Here we show that β amyloid increases somatostatin and cortistatin gene expression mainly through an increase in histone 3 lysine 4 methylation (H3K4me3), a modification associated with transcriptional activation. Somatostatin and cortistatin partially decreased β amyloid toxicity in primary cortical neurons in culture. Thus we suggest that neurons respond to β amyloid insults by releasing somatostatin and cortistatin, which will act as a protective agent against β amyloid toxicity. Our results suggest a relevant function for both neuropeptides against β amyloid toxicity, providing new insights into Alzheimer's disease. © 2011 Wiley Periodicals, Inc.