Alzheimer's disease (AD) is a senile dementia characterized by amyloid plaques, neurofibrillary tangles, and synaptic and cell loss. The “amyloid cascade” hypothesis suggests that amyloid-β (Aβ), the peptide deposited as amyloid plaques, is the primary insult in AD. However, debate continues over the mechanism of Aβ toxicity and whether fibrillar or oligomeric Aβ is the active species of the peptide that ultimately causes the synaptic loss and dementia associated with AD. Brain-derived neurotrophic factor (BDNF) is required for survival and function of cells compromised in AD. Decreased BDNF causes defects in long-term potentiation and memory and correlates with cognitive decline. We previously demonstrated that BDNF reduction occurs early in the course of AD, suggesting that decreased BDNF may promote neuronal dysfunction in AD. We also demonstrated that three of seven human BDNF transcripts are specifically downregulated in AD. What pathological feature(s) of AD leads to the decreased BDNF is unknown.

In this study, we administered both fibrillar and oligomeric conformations of Aβ_1–42 to differentiated SH-SY5Y, a human neuroblastoma cell line, and measured both phosphorylated cAMP response element-binding protein (CREB), a regulator of BDNF transcription, and BDNF total mRNA. We found that oligomeric but not fibrillar preparations of Aβ_1–42 significantly decrease both phosphorylated CREB and total BDNF mRNA. Furthermore, oligomeric Aβ_1–42 decreases BDNF transcripts IV and V in these cells, demonstrating that Aβ_1–42 downregulates the major BDNF transcript decreased in vivo in the AD brain. Thus, oligomeric Aβ_1–42 could compromise neuronal function, causing memory loss and cognitive dysfunction by downregulation of BDNF in AD.