Brain-derived neurotrophic factor reduces amyloidogenic processing through control of SORLA gene expression

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Sorting protein-related receptor with A-type repeats (SORLA) is implicated in Alzheimer's disease (AD) pathogenesis.
• SORLA regulates amyloid precursor protein (APP) trafficking and processing into amyloid-beta (Aβ) peptides.
• Reduced SORLA expression is linked to increased amyloidogenic processing in AD.

Purpose of the Study:

• Identify molecular pathways controlling SORLA gene transcription in vivo.
• Investigate the role of brain-derived neurotrophic factor (BDNF) in SORLA regulation.
• Determine if BDNF influences amyloidogenic processing via SORLA.

Main Methods:

• Screening approaches in primary neurons.
• Analysis of SORLA gene transcription.
• Assessment of Aβ production in neuronal cultures and mouse models.
• Utilized genetic knock-out and disease models (Bdnf(-/-)), Huntington's disease models.

Main Results:

• Brain-derived neurotrophic factor (BDNF) identified as a key inducer of SORLA gene transcription.
• BDNF activates SORLA transcription via the ERK pathway.
• SORLA expression is impaired in mouse models with reduced BDNF activity.
• Exogenous BDNF application reduced Aβ production in wild-type mice, but not in SORLA-deficient animals.

Conclusions:

• BDNF induces SORLA transcription, acting as a negative regulator of neuronal APP processing.
• The therapeutic effects of BDNF in APP metabolism are mediated through SORLA induction.
• This pathway represents a potential therapeutic target for Alzheimer's disease.