Coenzyme Q10 Restores Amyloid Beta-Inhibited Proliferation of Neural Stem Cells by Activating the PI3K Pathway

Abstract

Neurogenesis in the adult brain is important for memory and learning, and the alterations in neural stem cells (NSCs) may be an important part of Alzheimer's disease pathogenesis. The phosphatidylinositol 3-kinase (PI3K) pathway has been suggested to play an important role in neuronal cell survival and is highly involved in adult neurogenesis. Recently, coenzyme Q10 (CoQ10) was found to affect the PI3K pathway. We investigated whether CoQ10 could restore amyloid β (Aβ)25-35 oligomer-inhibited proliferation of NSCs by focusing on the PI3K pathway. To evaluate the effects of CoQ10 on Aβ25-35 oligomer-inhibited proliferation of NSCs, NSCs were treated with several concentrations of CoQ10 and/or Aβ25-35 oligomers. BrdU labeling, Colony Formation Assays, and immunoreactivity of Ki-67, a marker of proliferative activity, showed that NSC proliferation decreased with Aβ25-35 oligomer treatment, but combined treatment with CoQ10 restored it. Western blotting showed that CoQ10 treatment increased the expression levels of p85α PI3K, phosphorylated Akt (Ser473), phosphorylated glycogen synthase kinase-3β (Ser9), and heat shock transcription factor, which are proteins related to the PI3K pathway in Aβ25-35 oligomers-treated NSCs. To confirm a direct role for the PI3K pathway in CoQ10-induced restoration of proliferation of NSCs inhibited by Aβ25-35 oligomers, NSCs were pretreated with a PI3K inhibitor, LY294002; the effects of CoQ10 on the proliferation of NSCs inhibited by Aβ25-35 oligomers were almost completely blocked. Together, these results suggest that CoQ10 restores Aβ25-35 oligomer-inhibited proliferation of NSCs by activating the PI3K pathway.

The role of PI3K/AKT pathway and its therapeutic possibility in Alzheimer's disease

“…Based on our previous studies, the PI3K/AKT pathway is inhibited by Aβ and its recovery by diverse ways is helpful for the prevention of Aβ toxicity [14,15,54]. This finding is also supported by many other researchers [55][56][57].…”

“…Therefore, GSK-3β inhibition through the activation of PI3K/AKT can be another solution for the treatment of AD. We have reported that GV1001, which is a novel vaccine peptide mimicking Human telomerase reverse transcriptase (hTERT), donepezil, and coenzyme Q10 can block Aβ through the activation of PI3K and AKT and then the inhibition of GSK-3β [14,54,67]. Although the Phase II clinical trial using NP031112, a GSK-3β inhibitor, has not yet shown definite efficacy to AD patients, it showed that its usage was safe.…”

“…Describing in detail, ischemia in the brain and oxidative stress inhibit the PI3K/AKT pathway in neurons and neural stem cells and then induce cell death, so there have been a lot of studies to develop the way to protect neurons and neural stem cells by activating the pathway [10][11][12][13]. This phenomenon also happens in amyloid-induced cell death [14,15]. Considering the importance of the PI3K/AKT pathway in cell survival and growth, finding a good way to activate the pathway might be another option for the treatment of AD.…”

Neuroprotective Effects of Sulforaphane on Cholinergic Neurons in Mice with Alzheimer’s Disease-Like Lesions

“…The proliferation of neurocytes in these regions has been studied in various AD mouse models, but the findings have been inconsistent. Although an overall trend of impaired neurocyte proliferation in these areas in AD has been documented [32,33,34,35], Kamphuis et al . [36] and Díaz-Moreno et al [37] observed enhanced proliferation in APP/PS1 and SAMP8 mice, respectively.…”

Influence of Chronic Coenzyme Q10 Supplementation on Cognitive Function, Learning, and Memory in Healthy and Diabetic Middle-Aged Rats

“…In addition, CoQ10 oral administration restores oxygen consumption levels in the brain of aged animals [74] and exerts antihyperglycemic effects [23-25]. In addition, previous reports have indicated the usefulness of CoQ10 supplementation on memory processing by improving hippocampal cholinergic function via increasing cholineacetyltransferase and decreasing acetylcholinesterase activities [53], neurogenesis via reducing amyloid-β formation [75, 76], reducing oxidative stress markers, and increasing ATP levels in hippocampus and cortex [53]. Therefore, the sum of CoQ10 supplementation on decline of hyperglycemia, oxidative stress, neuronal apoptosis, and improved cholinergic activity, vascular function, brain blood flow, and metabolism may contribute to the attenuation of DM-induced memory impairment in the present study.…”