Regulatory factor X1 depresses ApoE-dependent Aβ uptake by miRNA-124 in microglial response to oxidative stress

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Soluble amyloid beta (Aβ) clearance by microglia is crucial for Alzheimer's disease (AD) progression.
• The precise molecular mechanisms governing microglial Aβ uptake remain incompletely understood.
• Aging is associated with impaired microglial function and increased Aβ accumulation.

Purpose of the Study:

• To elucidate the role of microRNA-124 (miR-124) in regulating apolipoprotein E (ApoE)-dependent Aβ uptake in microglia.
• To identify the molecular targets and signaling pathways involved in miR-124-mediated regulation of Aβ clearance.
• To investigate the potential of targeting this pathway for therapeutic interventions in AD.

Main Methods:

• Utilized BV2 microglia cell line for in vitro studies.
• Investigated the effect of miR-124 down-regulation on Aβ uptake under oxidative stress (hydrogen peroxide).
• Employed techniques to identify microRNA and protein binding sites, including 3'-UTR analysis and gene intron analysis.
• Performed gene knockdown experiments (RFX1) to assess functional impact on Aβ uptake.

Main Results:

• miR-124 was found to be down-regulated in aging and under oxidative stress.
• miR-124 targets regulatory factor X1 (RFX1) transcripts, inhibiting its protein expression.
• Decreased miR-124 led to increased RFX1 protein and reduced ApoE expression, impairing Aβ uptake.
• Identified specific binding sites for miR-124 on RFX1 mRNA and RFX1 on the ApoE gene.
• Knockdown of RFX1 significantly enhanced Aβ uptake in microglia.

Conclusions:

• Decreased miR-124 expression under oxidative stress impairs microglial Aβ uptake by increasing RFX1 and decreasing ApoE.
• The miR-124/RFX1/ApoE signaling axis represents a novel mechanism regulating microglial Aβ clearance.
• RFX1 inhibition presents a potential therapeutic target for enhancing Aβ clearance in aging and Alzheimer's disease.