Ruscus aculeatus Extract Inhibits Amyloid Beta Production and Upregulates the Active form of ADAM10 in Human Neural Progenitor Cells

Abstract Alzheimer’s disease is characterized by the accumulation of cerebral amyloid beta (Aβ) peptides, making the inhibition of Aβ production a key therapeutic strategy. We screened a plant extract library for Aβ42 inhibitors using human neural progenitor cells and identified a Ruscus aculeatus extract as a potential candidate. Although rhizome extracts of R. aculeatus exhibit vasotonic, and anti-inflammatory properties, their effects on amyloid-β precursor protein (APP) processing have not been investigated. We aimed to elucidate how R. aculeatus extract influences Aβ production and its underlying mechanisms. R. aculeatus extract significantly reduced Aβ40 and Aβ42 production and the pathogenic Aβ42/Aβ40 ratio in both human neural progenitor (ReNcell VM) and mouse neuroblastoma (Neuro2a) cells in concentration-dependent manner. The extract enhanced non-amyloidogenic APP pathway processing, evidenced by increased levels of ADAM10 active form, soluble APPα and C-terminal fragment α levels. Despite increasing BACE1 protein levels, the extract reduced soluble APPβ production, suggesting inhibition of BACE1-mediated APP cleavage. RNA-seq analysis revealed Notch signaling pathway downregulation, implying γ-secretase activity modulation. In conclusion, the R. aculeatus extract suppresses Aβ production by modulating multiple APP processing pathways, primarily through enhancing non-amyloidogenic pathway via ADAM10 activation. By reducing amyloidogenic peptides levels, R. aculeatus extract may contribute to decreased amyloid plaques formation. These findings identify R. aculeatus extract as a modulator of APP metabolism.