High intracellular concentrations of amyloid-beta block nuclear translocation of phosphorylated CREB

The beta-amyloid peptide (A beta) is considered responsible for the pathogenesis of Alzheimer's disease. Despite the magnitude of reports describing a neurotoxic role of extracellular AP, the role for intracellular A beta (iA beta) has not been elucidated. We previously demonstrated that in rat pheochromocytoma cells expression of moderate levels of AP results in the up-regulation of phospho-extracellular signal-regulated kinases (ERK1)/2 along with an elevation of cyclic AMP-response element (CRE)-regulated gene expression; however, the effect of high intracellular levels of AP were not examined. Towards this goal we generated constructs that endogenously produce different expression levels of iA beta in a human cell line. We show a bimodal response to iA beta in a neural human cell line. A moderate increase of endogenous A beta up-regulates certain cyclic AMP-response element-binding protein (CREB) responsive genes such as presenilin 1, presenilin 2, brain-derived neurotrophic factor, and mRNA and protein levels by CREB activation and Synapsin 1 nuclear translocation. On the other hand, high-loads of A beta resulted in sustained hyper-phosphorylation of CREB that did not translocate to the nucleus and did not stimulate activation of CRE-regulated gene expression. Our study suggests that variations in levels of iA beta could influence signaling mechanisms that lead to phosphorylation of CREB, its nuclear translocation and CRE-regulated genes involved in production of A beta and synaptic plasticity in opposite directions.