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

Abstract：

:The beta-amyloid peptide (Abeta) is considered responsible for the pathogenesis of Alzheimer's disease. Despite the magnitude of reports describing a neurotoxic role of extracellular Abeta, the role for intracellular Abeta (iAbeta) has not been elucidated. We previously demonstrated that in rat pheochromocytoma cells expression of moderate levels of Abeta 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 Abeta were not examined. Towards this goal we generated constructs that endogenously produce different expression levels of iAbeta in a human cell line. We show a bimodal response to Abeta in a neural human cell line. A moderate increase of endogenous Abeta 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 iAbeta 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 iAbeta could influence signaling mechanisms that lead to phosphorylation of CREB, its nuclear translocation and CRE-regulated genes involved in production of Abeta and synaptic plasticity in opposite directions.

journal_name

J Neurochem

journal_title

Journal of neurochemistry

authors

Arvanitis DN,Ducatenzeiler A,Ou JN,Grodstein E,Andrews SD,Tendulkar SR,Ribeiro-da-Silva A,Szyf M,Cuello AC

doi

10.1111/j.1471-4159.2007.04704.x

subject

Has Abstract

pub_date

2007-10-01 00:00:00

pages

216-28

issue

1

eissn

0022-3042

issn

1471-4159

pii

JNC4704

journal_volume

103

pub_type

杂志文章

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