We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
High intracellular concentrations of amyloid-beta block nuclear translocation of phosphorylated CREB.
- Authors
Arvanitis, D. N.; Ducatenzeiler, A.; Ou, J. N.; Grodstein, E.; Andrews, S. D.; Tendulkar, S. R.; Ribeiro-da-Silva, A.; Szyf, M.; Cuello, A. C.
- Abstract
The beta-amyloid peptide (Aβ) is considered responsible for the pathogenesis of Alzheimer’s disease. Despite the magnitude of reports describing a neurotoxic role of extracellular Aβ, the role for intracellular Aβ (iAβ) has not been elucidated. We previously demonstrated that in rat pheochromocytoma cells expression of moderate levels of Aβ 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 Aβ were not examined. Towards this goal we generated constructs that endogenously produce different expression levels of iAβ in a human cell line. We show a bimodal response to Aβ in a neural human cell line. A moderate increase of endogenous Aβ 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 iAβ 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 iAβ could influence signaling mechanisms that lead to phosphorylation of CREB, its nuclear translocation and CRE-regulated genes involved in production of Aβ and synaptic plasticity in opposite directions.
- Subjects
AMYLOID beta-protein; PEPTIDES; CHROMOSOMAL translocation; CYCLIC adenylic acid; CARRIER proteins
- Publication
Journal of Neurochemistry, 2007, Vol 103, Issue 1, p216
- ISSN
0022-3042
- Publication type
Article
- DOI
10.1111/j.1471-4159.2007.04704.x