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Endogenous beta-amyloid peptide synthesis modulates cAMP response element-regulated gene expression in PC12 cells.

V Echeverria·A Ducatenzeiler·C H Chen·A C Cuello
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Abstract

Extracellular-regulated kinases play a fundamental role in several neuroplasticity processes. In order to test whether endogenous beta-amyloid peptides play a role in the activation of extracellular-regulated kinase, we investigated the Rap1-extracellular-regulated kinase pathway in PC12 cells expressing human beta-amyloid precursor protein containing familial Alzheimer's disease mutations. In PC12 cells transfected with mutant human beta-amyloid precursor proteins that lead to higher levels of endogenous beta-amyloid, we observed an up-regulation of phospho-extracellular-regulated kinase and higher levels of activity-induced cAMP response element-directed gene expression. These results suggest that moderate levels of endogenous beta-amyloid peptides stimulate cAMP response element-directed gene expression. This stimulation was via a Rap1/MEK/extracellular-regulated kinase signaling pathway, as it was blocked by inhibition of Rap1 and MEK activities, and it requires beta-amyloid precursor protein cleavage at the gamma-site as it was abolished by a gamma-secretase inhibitor. Interestingly, in agreement with the previous observations, micromolar levels of extracellular fibrillar beta-amyloid blocked the cAMP response element-regulated gene expression stimulated by potassium and forskolin. This indicates that beta-amyloid can provoke different responses on cAMP response element-directed gene expression, such that low beta-amyloid levels may play a physiological role favoring synaptic plasticity under normal conditions while it would inhibit this mechanism under pathological conditions.

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Alzheimer DiseaseAmyloid Precursor Protein SecretasesAmyloid beta-Protein PrecursorAnimalsAspartic Acid EndopeptidasesBlotting, WesternCyclic AMP Response Element-Binding ProteinEndopeptidasesEnzyme InhibitorsExtracellular Signal-Regulated MAP KinasesGene ExpressionHumansMAP Kinase Kinase KinasesModels, BiologicalMutationPC12 CellsPhosphorylationRatsTransfectionrap1 GTP-Binding ProteinsJournal ArticleResearch Support, Non-U.S. Gov't

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V Echeverria, A Ducatenzeiler, C H Chen, A C Cuello. 2005-09-21. Endogenous beta-amyloid peptide synthesis modulates cAMP response element-regulated gene expression in PC12 cells.. https://doi.org/10.1016/j.neuroscience.2005.06.057

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