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

Extracellular-regulated kinases play a fundamental role in several neuroplasticity processes. In order to test whether endogenous β-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 β-amyloid precursor protein containing familial Alzheimer's disease mutations. In PC12 cells transfected with mutant human β-amyloid precursor proteins that lead to higher levels of endogenous β-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 β-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 β-amyloid precursor protein cleavage at the γ-site as it was abolished by a γ-secretase inhibitor. Interestingly, in agreement with the previous observations, micromolar levels of extracellular fibrillar β-amyloid blocked the cAMP response element-regulated gene expression stimulated by potassium and forskolin. This indicates that β-amyloid can provoke different responses on cAMP response element-directed gene expression, such that low β-amyloid levels may play a physiological role favoring synaptic plasticity under normal conditions while it would inhibit this mechanism under pathological conditions.