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

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is the leading cause of dementia, affecting nearly 55 million people across the world. One of the central pathological factors associated with AD is the aggregation of Aβ₄₂, a peptide product cleaved through pathological processes in AD. Under pathological conditions, Aβ₄₂ aggregates into insoluble plaques in the brain and impairs the function of neurons, which contributes to the cognitive decline associated with AD. Therefore, the modulation of Aβ₄₂ aggregation is considered a potential therapeutic intervention for AD. Using an Oligoquinoline-based foldamer library, we have identified a potent foldamer antagonist (SK-131) of Aβ₄₂ aggregation. SK-131 inhibits the aggregation by inducing a α-helical structure in monomeric Aβ₄₂. Here, we demonstrated that SK-131 rescues Aβ₄₂ aggregation-associated phenotypes in AD cellular and multiple Caenorhabditis elegans AD models, including intracellular inhibition of Aβ₄₂ aggregation, rescue of behavioral deficits, and attenuation of reactive oxygen species. It efficiently crosses the blood-brain barrier and demonstrates favorable pharmaceutical properties. It also potently inhibits Zn²⁺-mediated Aβ₄₂ aggregation by potentially displacing Zn²⁺ from Aβ₄₂. In summary, we have identified a potent brain-penetrating foldamer that efficiently rescues AD phenotypes in in vivo models. Unlike most of the therapeutic approaches that target Aβ aggregates, we have identified and validated a novel therapeutic pathway by inducing structural change in Aβ and rescuing AD phenotypes in in vivo models. This study will further aid in the quest to identify lead therapeutics to slow or stop the progression of AD.

Keywords: Alzheimer’s disease; aggregation; foldamers; neurodegeneration; protein−protein interaction; synthetic protein mimetics.