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

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) (Aβ(25-35)) oligomer-inhibited proliferation of NSCs by focusing on the PI3K pathway. METHODS: To evaluate the effects of candesartan on the Aβ(25-35) oligomer-inhibited proliferation of NSCs, the NSCs were treated with several concentrations of candesartan and/or Aβ(25-35) 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 Aβ(25-35) 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 Aβ(25-35) oligomers were almost completely blocked. CONCLUSIONS: Together, these results suggest that candesartan restores the Aβ(25-35) oligomer-inhibited proliferation of NSCs by activating the PI3K pathway.