CREB expression mediates amyloid β-induced basal BDNF downregulation

In Alzheimer's disease, accumulation of amyloid-beta (A beta) is associated with loss of brain-derived neurotrophic factor (BDNF), synapses, and memory. Previous work demonstrated that A beta decreases activity-induced BDNF transcription by regulating cyclic adenosine monophosphate response element binding protein (CREB) phosphorylation. However, the specific mechanism by which A beta reduces basal BDNF expression remains unclear. Differentiated, unstimulated human neuroblastoma (SH-SY5Y) cells treated with oligomeric A beta exhibited significantly reduced CREB messenger RNA compared with controls. Phosphorylated and total CREB proteins were decreased in both the cytoplasm and nucleus of A beta-treated cells. However, neither pCREB129 nor pCREB133 levels were altered relative to total CREB levels. The protein kinase A activator forskolin increased pCREB133 levels and prevented A beta-induced basal BDNF loss when administered before A beta but did not rescue BDNF expression when administered later. These data demonstrate a new mechanism for A beta-induced BDNF downregulation: in the absence of cell stimulation, A beta downregulates basal BDNF levels via A beta-induced CREB transcriptional downregulation, not changes in CREB phosphorylation. Thus, A beta reduces basal and activity-induced BDNF expression by different mechanisms. (C) 2015 Elsevier Inc. All rights reserved.