DNA Aptamers Targeting BACE1 Reduce Amyloid Levels and Rescue Neuronal Deficiency in Cultured Cells

Area of Science:

• Biochemistry
• Molecular Biology
• Neuroscience

Background:

• Alzheimer's disease (AD) pathogenesis involves beta-amyloid (Aβ) accumulation.
• Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is crucial for Aβ production.
• Targeting BACE1 is a promising therapeutic strategy for AD, but its large active site poses challenges for small-molecule inhibitors.

Purpose of the Study:

• To develop specific DNA aptamers targeting BACE1 for potential AD therapy.
• To investigate the efficacy of DNA aptamers in inhibiting BACE1 activity and reducing Aβ production.
• To evaluate the therapeutic potential of BACE1-targeting DNA aptamers in neuronal models.

Main Methods:

• A novel cell-systematic evolution of ligands by exponential enrichment (SELEX) strategy was employed to select BACE1-specific DNA aptamers.
• Selected aptamers (BI1 and BI2) were validated using pull-down assays, in vitro FRET assays, and cell-based assays with HEK293-APP and APP-PS1 neurons.
• Aβ levels and neuronal function were assessed in response to aptamer treatment.

Main Results:

• Two high-affinity DNA aptamers, BI1 and BI2, were identified against BACE1.
• These aptamers demonstrated BACE1 inhibition in vitro and in cell-based assays, reducing Aβ production in cell culture and primary neurons.
• The aptamers rescued Aβ-induced neuronal deficiency without affecting α- or γ-secretase activity. TEG modification enhanced aptamer potency.

Conclusions:

• DNA aptamers represent a feasible and effective strategy for targeting BACE1.
• The identified BACE1-specific DNA aptamers hold therapeutic potential for Alzheimer's disease.
• Further investigation into the therapeutic applications of these aptamers is warranted.