Ginkgo Biloba Extract Ameliorates Oxidative Phosphorylation Performance and Rescues Aβ-Induced Failure

Abstract

BackgroundEnergy deficiency and mitochondrial failure have been recognized as a prominent, early event in Alzheimer's disease (AD). Recently, we demonstrated that chronic exposure to amyloid-beta (Aβ) in human neuroblastoma cells over-expressing human wild-type amyloid precursor protein (APP) resulted in (i) activity changes of complexes III and IV of the oxidative phosphorylation system (OXPHOS) and in (ii) a drop of ATP levels which may finally instigate loss of synapses and neuronal cell death in AD. Therefore, the aim of the present study was to investigate whether standardized Ginkgo biloba extract LI 1370 (GBE) is able to rescue Aβ-induced defects in energy metabolism.Methodology/Principal FindingsWe used a high-resolution respiratory protocol to evaluate OXPHOS respiratory capacity under physiological condition in control (stably transfected with the empty vector) and APP cells after treatment with GBE. In addition, oxygen consumption of isolated mitochondria, activities of mitochondrial respiratory enzymes, ATP and reactive oxygen species (ROS) levels as well as mitochondrial membrane mass and mitochondrial DNA content were determined. We observed a general antioxidant effect of GBE leading to an increase of the coupling state of mitochondria as well as energy homeostasis and a reduction of ROS levels in control cells and in APP cells. GBE effect on OXPHOS was even preserved in mitochondria after isolation from treated cells. Moreover, these functional data were paralleled by an up-regulation of mitochondrial DNA. Improvement of the OXPHOS efficiency was stronger in APP cells than in control cells. In APP cells, the GBE-induced amelioration of oxygen consumption most likely arose from the modulation and respective normalization of the Aβ-induced disturbance in the activity of mitochondrial complexes III and IV restoring impaired ATP levels possibly through decreasing Aβ and oxidative stress level.Conclusions/SignificanceAlthough the underlying molecular mechanisms of the mode of action of GBE remain to be determined, our study clearly highlights the beneficial effect of GBE on the cellular OXPHOS performance and restoration of Aβ-induced mitochondrial dysfunction.

Metabolic Characterization of Intact Cells Reveals Intracellular Amyloid Beta but Not Its Precursor Protein to Reduce Mitochondrial Respiration

“…Therefore, we addressed this question in the present study by elevating APP and Aβ levels or Aβ levels alone in two distinct cell lines by the overexpression of APP or BACE1, respectively. Similar to other studies [25, 27, 28, 39] we observed a reduced mitochondrial respiration in cell lines overexpressing APP although the magnitude of reduction in our cells was lower. This could be due to the moderate increase in APP expression levels or due to the fact that we performed respirometry of intact instead of permeabilized cells.…”

Effects of standardized extract of Ginkgo biloba leaves EGb761 on mitochondrial functions: mechanism(s) of action and dependence on the source of mitochondria and respiratory substrate

“…Interesting data on the action/effects of EGB on different mitochondrial respiratory parameters and respiratory chain complexes were obtained by Rhein et al (2010) but due to different subjects investigated (human neuroblastoma cells in work of Rhein et al), different EGb preparations (EGb LI 1370), time of treatment and different compositions of media used for respiration measurements data comparison and analysis of reasons of differences of effects obtained in the work mentioned above and in our study is hardly possible. Fig.…”

Drosophila melanogaster: Deciphering Alzheimer's Disease

“…Ginkgo biloba improves metabolic energy pathways through enhancement of the mitochondrial coupling state. Furthermore, the model showed substantial results for Ginkgo biloba as a long term therapeutic drug for AD (75).…”