Fucoxanthin suppresses amyloid-β and pyroglutamate-3-Aβ accumulation by modulating the PI3K/Akt/GSK-3β signaling pathway

Abstract

Aberrant aggregation of amyloid-β (Aβ) peptides is a hallmark of Alzheimer's disease (AD), contributing to synaptic dysfunction and cognitive decline. Recently, pyroglutamate-modified Aβ (pE3-Aβ) has emerged as a key contributor to Aβ pathology, as it is a highly aggregation-prone variant that enhances amyloid seeding and accelerates plaque propagation. β-Secretase (BACE1) and glutaminyl cyclase (QC) are essential enzymes for generating Aβ and pE3-Aβ, respectively, and represent key therapeutic targets. This study evaluated fucoxanthin, a marine carotenoid found in brown algae for its potential to modulate Aβ pathology and cognitive function. In SweAPP N2a cells, fucoxanthin (0.1–5 μM) significantly decreased BACE1 and QC expression, accompanied by reduced levels of Aβ_1–42 and pE3-Aβ. Consistent with these changes, enhanced expression of ADAM10 and increased sAPPα secretion further supported a shift toward non-amyloidogenic APP processing by fucoxanthin. Fucoxanthin reduced both spontaneous and pE3-Aβ-seeded aggregation, reflecting its capacity to limit pathogenic amyloid assembly. Mechanistically, it activated Akt and inactivated GSK-3β, effects reversed by PI3K inhibition. In an Aβ_1–42-injected mouse model, used for rapid induction of early amyloid pathology, oral administration of fucoxanthin (100 or 200 mg kg⁻¹) improved memory performance, producing effects comparable to donepezil. Analysis of hippocampal tissue showed that inhibition of BACE1 and QC by fucoxanthin was associated with reduced Aβ and pE3-Aβ levels, consistent with cellular findings. These findings suggest that fucoxanthin exerts multi-targeted effects on Aβ-related pathology and supports its potential as a functional food component for the dietary prevention of early-stage AD.