Oligomeric amyloid decreases basal levels of brain-derived neurotrophic factor (BDNF) mRNA via specific downregulation of BDNF transcripts IV and V in differentiated human neuroblastoma cells.

ABSTRACT: 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-beta (Abeta), the peptide deposited as amyloid plaques, is the primary insult in AD. However, debate continues over the mechanism of Abeta toxicity and whether fibrillar or oligomeric Abeta 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 Abeta(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 Abeta(1-42) significantly decrease both phosphorylated CREB and total BDNF mRNA. Furthermore, oligomeric Abeta(1-42) decreases BDNF transcripts IV and V in these cells, demonstrating that Abeta(1-42) downregulates the major BDNF transcript decreased in vivo in the AD brain. Thus, oligomeric Abeta(1-42) could compromise neuronal function, causing memory loss and cognitive dysfunction by downregulation of BDNF in AD.

SUBMITTER: Garzon DJ 

PROVIDER: S-EPMC6672502 | biostudies-literature | 2007 Mar

REPOSITORIES: biostudies-literature