The Phosphatidyl Inositol 3 Kinase-Glycogen Synthase Kinase 3β Pathway Mediates Bilobalide-Induced Reduction in Amyloid β-Peptide

Bilobalide (BB), a sesquiterpenoid extract of Ginkgo biloba leaves, has been demonstrated to have neuroprotective effects. The neuroprotective mechanisms were suggested to be associated with modulation of intracellular signaling cascades such as the phosphatidyl inositol 3-kinase (PI3K) pathway. Since some members of intracellular signalling pathways such as PI3K have been demonstrated to be involved in amyloid precursor protein (APP) processing, the present study investigated whether BB has an influence on the beta-secretase-mediated APP cleavage via PI3K-dependent pathway. Using HT22 cells and SAMP8 mice (a senescence-accelerated strain of mice), this study showed that BB treatment reduced generation of two beta-secretase cleavage products of APP, the amyloid beta-peptide (A beta) and soluble APP beta (sAPP beta), via PI3K-dependent pathway. Additionally, glycogen synthase kinase 3 beta (GSK3 beta) signaling might be involved in BB-induced A beta reduction as a downstream target of the activated PI3K pathway. BB showed no significant effects on beta-site APP cleaving enzyme 1 (BACE-1) or gamma-secretase but inhibited the beta-secretase activity of another protease cathepsin B, suggesting that BB-induced A beta reduction was probably mediated through modulation of cathepsin B rather than BACE-1. Similarly, inhibition of GSK3b did not affect BACE-1 activity but decreased cathepsin B activity, suggesting that the PI3K-GSK3 beta pathway was probably involved in BB-induced A beta reduction. Increasing evidence suggests that decreasing A beta production in the brain via modulation of APP metabolism should be beneficial for the prevention and treatment of Alzheimer's disease (AD). BB may offer such an approach to combat AD.