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

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 Aβ1-42 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 Aβ1-42-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.