Dieckol Ameliorates Aβ Production via PI3K/Akt/GSK-3β Regulated APP Processing in SweAPP N2a Cell

초록

The proteolytic processing of amyloid precursor protein (APP) by beta-secretase (BACE1) and gamma-secretase releases amyloid-beta peptide (A beta), which deposits in amyloid plaques and contributes to the initial causative events of Alzheimer's disease (AD). In the present study, the regulatory mechanism of APP processing of three phlorotannins was elucidated in Swedish mutant APP overexpressed N2a (SweAPP N2a) cells. Among the tested compounds, dieckol exhibited the highest inhibitory effect on both intra- and extracellular A beta accumulation. In addition, dieckol regulated the APP processing enzymes, such as alpha-secretase (ADAM10), beta-secretase, and gamma-secretase, presenilin-1 (PS1), and their proteolytic products, sAPP alpha and sAPP beta, implying that the compound acts on both the amyloidogenic and non-amyloidogenic pathways. In addition, dieckol increased the phosphorylation of protein kinase B (Akt) at Ser473 and GSK-3 beta at Ser9, suggesting dieckol induced the activation of Akt, which phosphorylated GSK-3 beta. The specific phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 triggered GSK-3 beta activation and A beta expression. In addition, co-treatment with LY294002 noticeably blocked the effect of dieckol on A beta production, demonstrating that dieckol promoted the PI3K/Akt signaling pathway, which in turn inactivated GSK-3 beta, resulting in the reduction in A beta levels.

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