CREB expression mediates amyloid β-induced basal BDNF downregulation

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• Alzheimer's disease (AD) involves amyloid-β (Aβ) accumulation, linked to memory loss and reduced brain-derived neurotrophic factor (BDNF).
• Aβ impairs activity-induced BDNF transcription by altering CREB phosphorylation, but the mechanism for basal BDNF reduction is unknown.

Purpose of the Study:

• To elucidate the mechanism by which Aβ reduces basal BDNF expression in human neuroblastoma cells.

Main Methods:

• Treatment of differentiated SH-SY5Y cells with oligomeric Aβ.
• Quantification of CREB messenger RNA and protein levels (total and phosphorylated).
• Assessment of BDNF expression and effects of forskolin, a protein kinase A activator.

Main Results:

• Oligomeric Aβ significantly reduced CREB messenger RNA levels in unstimulated cells.
• Both phosphorylated and total CREB proteins decreased in cytoplasm and nucleus, without altering relative phosphorylation levels.
• Forskolin prevented Aβ-induced basal BDNF loss when applied before Aβ, but not when applied later.

Conclusions:

• Aβ downregulates basal BDNF by reducing CREB transcriptional activity, independent of CREB phosphorylation changes.
• This represents a novel mechanism distinct from Aβ's effect on activity-induced BDNF.
• Aβ differentially regulates basal and activity-induced BDNF expression through separate pathways.