A Brain-Penetrating Foldamer Rescues Aβ Aggregation-Associated Alzheimer's Disease Phenotypes in In Vivo Models

Area of Science:

• Neuroscience
• Biochemistry
• Pharmacology

Background:

• Alzheimer's disease (AD) is a leading cause of dementia, characterized by amyloid-beta (Aβ) aggregation.
• Aβ₄₂ peptide aggregation into plaques impairs neuronal function and cognitive abilities.
• Modulating Aβ aggregation is a key therapeutic strategy for AD.

Purpose of the Study:

• To identify novel therapeutic agents targeting Aβ₄₂ aggregation.
• To investigate the efficacy of a novel foldamer, SK-131, in preclinical AD models.

Main Methods:

• Screening an Oligoquinoline-based foldamer library to identify Aβ₄₂ aggregation inhibitors.
• Assessing SK-131's mechanism of action, including its effect on Aβ structure and Zn²⁺-mediated aggregation.
• Evaluating SK-131's efficacy in cellular AD models and *Caenorhabditis elegans* AD models.

Main Results:

• SK-131 identified as a potent antagonist of Aβ₄₂ aggregation.
• SK-131 inhibits aggregation by inducing an α-helical structure in monomeric Aβ₄₂.
• SK-131 demonstrated efficacy in rescuing AD phenotypes, including reduced aggregation, improved behavior, and attenuated oxidative stress in vivo.

Conclusions:

• SK-131 is a potent, brain-penetrant foldamer that effectively rescues AD phenotypes in preclinical models.
• SK-131 represents a novel therapeutic approach by targeting Aβ structure rather than existing aggregates.
• This study validates a new therapeutic pathway for developing AD treatments.