High intracellular concentrations of amyloid-beta block nuclear translocation of phosphorylated CREB.
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.
Arvanitis
D N
DN
Department of Pharmacology & Therapeutics, McGill University, Montreal, Quebec, Canada.
Ducatenzeiler
A
A
Ou
J N
JN
Grodstein
E
E
Andrews
S D
SD
Tendulkar
S R
SR
Ribeiro-da-Silva
A
A
Szyf
M
M
Cuello
A C
AC
D021581:Active Transport, Cell Nucleus; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism*; D009154:Mutation; D016716:PC12 Cells; D010766:Phosphorylation; D051381:Rats
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D017362:Cyclic AMP Response Element-Binding Protein