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

Abstract

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 β-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 β-secretase cleavage products of APP, the amyloid β-peptide (Aβ) and soluble APPβ (sAPPβ), via PI3K-dependent pathway. Additionally, glycogen synthase kinase 3β (GSK3β) signaling might be involved in BB-induced Aβ reduction as a downstream target of the activated PI3K pathway. BB showed no significant effects on β-site APP cleaving enzyme 1 (BACE-1) or γ-secretase but inhibited the β-secretase activity of another protease cathepsin B, suggesting that BB-induced Aβ reduction was probably mediated through modulation of cathepsin B rather than BACE-1. Similarly, inhibition of GSK3β did not affect BACE-1 activity but decreased cathepsin B activity, suggesting that the PI3K-GSK3β pathway was probably involved in BB-induced Aβ reduction. Increasing evidence suggests that decreasing Aβ 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.

Tanshinone IIA promotes non-amyloidogenic processing of amyloid precursor protein in platelets via estrogen receptor signaling to phosphatidylinositol 3-kinase/Akt

“…These data suggest that Tan IIA modulates platelet APP metabolism, possibly through ER signaling to PI3K/Akt. In accordance with this finding, our previous studies demonstrated that treatment of HT22 cells, SH-SY5Y cells stably expressing the Swedish mutant APP and ovariectomized rats with phytoestrogens, such as ginsenoside Rg1 and bilobalide, increases the secretion of sAPPα, enhances α-secretase activity and decreases the production of Aβ via ER-mediated PI3K/Akt signaling (11)(12)(13).…”

Roles of Glycogen Synthase Kinase 3 in Alzheimer’s Disease

“…The automated high-throughput fluorescence-based imaging system demonstrated that the modulation of GSK-3 activity resulted in the perturbation of BACE1 localization/trafficking and extensive A secretion [97,98] whereas it seems no change in the AD brains for GSK 3 [99]. Several -secretase-related signaling pathway damage such as PI3K/AKT [100], Wnt [101], and Ca 2+ -dependent PKC [97,102] participate in the mechanism which -secretase-mediated by active GSK-3 leads to A production and accumulation.…”

Nebracetam Inhibited Hippocampus Neurons Injury Induced by Aβ25-35 in MRTF-A-CArG Manner via ERK1/2 Pathway

“…Previous studies have indicated that MRTF-A elevates SRF-driven transcription and enhances its stimulation by brain-derived neurotrophic factor (BDNF) in primary cortical neurons, which can regulate SRF and hence contributes to specific gene expression. ERK1/2 as an important approach to AD, the pathway is being widely studied [29][30][31][32]. Previous studies have demonstrated that this pathway can be involved in the regulation of synaptic structure and function [31,33].…”

“…ERK1/2 as an important approach to AD, the pathway is being widely studied [29][30][31][32]. Previous studies have demonstrated that this pathway can be involved in the regulation of synaptic structure and function [31,33]. Activation of ERK1/2 pathway plays a key role in the regulation of functional and structural synaptic plasticity [34].…”