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
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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-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 Aβ1–42to 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 Aβ1–42significantly decrease both phosphorylated CREB and total BDNF mRNA. Furthermore, oligomeric Aβ1–42decreases BDNF transcripts IV and V in these cells, demonstrating that Aβ1–42downregulates the major BDNF transcript decreasedin vivoin the AD brain. Thus, oligomeric Aβ1–42could compromise neuronal function, causing memory loss and cognitive dysfunction by downregulation of BDNF in AD.
