Repurposing FDA-approved compounds as modulators of amyloidogenic aggregation in prion-like neurodegenerative disease models

Introduction:
Amyloidogenic protein aggregation is central to prion and prion-like disorders, including Alzheimer’s disease and synucleinopathies. Safe, repurposed compounds capable of modulating early aggregation events are urgently needed.

Objectives:
To identify FDA-approved compounds and nutraceuticals that can modulate aggregation of amyloidogenic proteins in yeast, nematode, and in vitro models.

Methods:
We employed a yeast model of Aβ-promoted prion nucleation, C. elegans strains expressing aggregation-prone proteins (A53T α-synuclein, P301L tau), and in vitro aggregation assays. Tested compounds included valerian root extract (VRE), omega-3 fatty acids, their active components, and novel formulations (T3, T9, T32). Aggregation of tau, polyglutamine, PrP-derived peptides, and Aβ was monitored using Thioflavin T fluorescence and atomic force microscopy (AFM).

Results/Discussion:
T3 and omega-3 consistently suppressed Aβ-dependent prion nucleation in yeast and reduced α-synuclein-induced toxicity in nematodes. VRE effectively dissolved tau and polyQ aggregates in vitro and reduced Aβ-dependent nucleation in yeast. However, it promoted aggregation of PrP-derived peptides. AFM imaging confirmed that VRE disrupted Aβ fibrils, while omega-3 showed context-specific modulation depending on peptide and conditions. These results underscore the value of multi-model platforms for identifying aggregation modulators and illustrate the differential activity of compounds across protein targets and biological systems.

Conclusion:
Valerian root extract and omega-3 derivatives show promise as modulators of amyloidogenic protein aggregation. Their distinct effects across models and protein species highlight the importance of system-specific evaluation. Ongoing studies aim to validate their therapeutic potential in mammalian models.