CREB expression mediates amyloid β-induced basal BDNF downregulation

In Alzheimer's disease, accumulation of amyloid-β (Aβ) is associated with loss of brain-derived neurotrophic factor (BDNF), synapses, and memory. Previous work demonstrated that Aβ decreases activity-induced BDNF transcription by regulating cyclic adenosine monophosphate response element binding protein (CREB) phosphorylation. However, the specific mechanism by which Aβ reduces basal BDNF expression remains unclear. Differentiated, unstimulated human neuroblastoma (SH-SY5Y) cells treated with oligomeric Aβ exhibited significantly reduced CREB messenger RNA compared with controls. Phosphorylated and total CREB proteins were decreased in both the cytoplasm and nucleus of Aβ-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 Aβ-induced basal BDNF loss when administered before Aβ but did not rescue BDNF expression when administered later. These data demonstrate a new mechanism for Aβ-induced BDNF downregulation: in the absence of cell stimulation, Aβ downregulates basal BDNF levels via Aβ-induced CREB transcriptional downregulation, not changes in CREB phosphorylation. Thus, Aβ reduces basal and activity-induced BDNF expression by different mechanisms.