期刊
NEUROSCIENCE
卷 135, 期 4, 页码 1193-1202出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuroscience.2005.06.057
关键词
intracellular A beta; beta-amyloid; CRE-regulated gene expression; ERK; Alzheimer's disease; synaptic plasticity
Extracellular-regulated kinases play a fundamental role in several neuroplasticity processes. In order to test whether endogenous beta-amylolid peptides play a role in the activation of extracellular-regulated kinase, we investigated the Rapt-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 Rapt/MEK/extracellular-regulated kinase signaling pathway, as it was blocked by inhibition of Rapt 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. (c) 2005 Published by Elsevier Ltd on behalf of IBRO.
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