Dement Neurocogn Disord.  2017 Sep;16(3):64-71. 10.12779/dnd.2017.16.3.64.

Candesartan Restores the Amyloid Beta-Inhibited Proliferation of Neural Stem Cells by Activating the Phosphatidylinositol 3-Kinase Pathway

• Choi H
• Choi NY
• Lee KY
• Lee YJ
• Koh SH

• KMID: 2442818
• DOI: http://doi.org/10.12779/dnd.2017.16.3.64

Abstract

BACKGROUND AND PURPOSE
Neurogenesis in the adult brain is important for memory and learning, and the alterations in neural stem cells (NSCs) may be an important aspect of Alzheimer's disease (AD) pathogenesis. The phosphatidylinositol 3-kinase (PI3K) pathway has been suggested to have an important role in neuronal cell survival and is highly involved in adult neurogenesis. Candesartan is an angiotensin II receptor antagonist used for the treatment of hypertension and several studies have reported that it also has some neuroprotective effects. We investigated whether candesartan could restore the amyloid-β(25-35) (Aβ₂₅₋₃₅) oligomer-inhibited proliferation of NSCs by focusing on the PI3K pathway.
METHODS
To evaluate the effects of candesartan on the Aβ₂₅₋₃₅ oligomer-inhibited proliferation of NSCs, the NSCs were treated with several concentrations of candesartan and/or Aβ₂₅₋₃₅ oligomers, and MTT assay and trypan blue staining were performed. To evaluate the effect of candesartan on the Aβ-inhibited proliferation of NSCs, we performed a bromodeoxyuridine (BrdU) labeling assay. The levels of p85α PI3K, phosphorylated Akt (pAkt) (Ser473), phosphorylated glycogen sinthase kinase-3β (pGSK-3β) (Ser9), and heat shock transcription factor-1 (HSTF-1) were analyzed by Western blotting.
RESULTS
The BrdU assays demonstrated that NSC proliferation decreased with Aβ25-35 oligomer treatment; however, a combined treatment with candesartan restored it. Western blotting displayed that candesartan treatment increased the expression levels of p85α PI3K, pAkt (Ser473), pGSK-3β (Ser9), and HSTF. The NSCs were pretreated with a PI3K inhibitor, LY294002; the effects of candesartan on the proliferation of NSCs inhibited by Aβ₂₅₋₃₅ oligomers were almost completely blocked.
CONCLUSIONS
Together, these results suggest that candesartan restores the Aβ₂₅₋₃₅ oligomer-inhibited proliferation of NSCs by activating the PI3K pathway.

Keyword

candesartan; amyloid beta; neural stem cells

MeSH Terms

Adult
Alzheimer Disease
Amyloid*
Blotting, Western
Brain
Bromodeoxyuridine
Cell Survival
Glycogen
Hot Temperature
Humans
Hypertension
Learning
Memory
Neural Stem Cells*
Neurogenesis
Neurons
Neuroprotective Agents
Phosphatidylinositol 3-Kinase*
Phosphatidylinositols*
Receptors, Angiotensin
Shock
Trypan Blue
Amyloid
Bromodeoxyuridine
Glycogen
Neuroprotective Agents
Phosphatidylinositol 3-Kinase
Phosphatidylinositols
Receptors, Angiotensin
Trypan Blue

Figure

• 

  Fig. 1 Viability of neural stem cells (NSCs) injured by the Aβ25-35 oligomer. The data are means (% of control)±standard deviations from five independent experiments. Treatment groups were compared with the control group using a Tukey's test after a one-way analysis of variance. The MTT assay and trypan blue staining (TBS) exhibit that the viability of NSCs decreased in a concentration-dependent manner when the cells were treated with more than 10 µM Aβ25-35 oligomer. *p<0.05 and †p<0.01 (vs. control group).

• 

  Fig. 2 Proliferation of neural stem cells (NSCs) injured by the Aβ25-35 oligomer. The data are means (% of control)±standard deviations from five independent experiments. The treatment groups were compared with the control group using a Tukey's test after a one-way analysis of variance. The BrdU assay displayed that the proliferation of NSCs decreased in a concentration-dependent manner when the cells were treated with more than 5 µM Aβ25-35 oligomer. *p<0.05 and †p<0.01 (vs. control group).

• 

  Fig. 3 Effect of candesartan on the proliferation of neural stem cells (NSCs) injured by Aβ25-35 oligomer. The data are means (% of control)±standard deviations from five independent experiments. The treatment groups were compared with the control group using a Tukey's test after a one-way analysis of variance. The BrdU assay displayed that treatment with candesartan restored the proliferation of NSCs inhibited by 10 µM Aβ25-35 oligomers. *p<0.05 and †p<0.01 (vs. control group), ‡p<0.01 and §p<0.01 (vs. the group treated with only 10 µM Aβ25-35 oligomer).

• 

  Fig. 4 Role of PI3K activation in the effect of candesartan on the proliferation of neural stem cells (NSCs) injured by Aβ25-35 oligomer. The data are means (% of control)±standard deviations from five independent experiments. The treatment groups were compared with the control group using a Tukey's test after a one-way analysis of variance. The BrdU assay displayed that co-treatment with LY294002 almost completely blocked the effect of candesartan on the proliferation of NSCs inhibited by 10 µM Aβ25-35 oligomer. *p<0.05 (vs. control group), ‡p<0.05 (vs. the group without the treatment of 10 µM LY294002).

• 

  Fig. 5 Effect of candesartan on the proliferation-related intracellular signaling proteins of neural stem cells (NSCs) injured by Aβ25-35 oligomer. The data are means (% of control)±standard deviations from five independent experiments. The treatment groups were compared with the control group using a Tukey's test after a one-way analysis of variance. Western blotting demonstrated that treatment with candesartan significantly enhanced the expression of the proliferation-related intracellular signaling proteins of NSCs inhibited by 10 µM Aβ25-35 oligomer. *p<0.05 and †p<0.01 (vs. control group), ‡p<0.01 and §p<0.01 (vs. the group treated with only 10 µM Aβ25-35 oligomer).

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