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Neuroprotection by aripiprazole against ?-amyloid-induced toxicity by P-CK2? activation via inhibition of GSK-3?.

ABSTRACT: Psychosis is reported over 30% of patients with Alzheimer's disease (AD) in clinics. Aripiprazole is an atypical antipsychotic drug with partial agonist activity at the D2 dopamine and 5-HT1A receptors with low side-effect profile. We identified aripiprazole is able to overcome the amyloid-? (A?)-evoked neurotoxicity and then increase the cell viability. This study elucidated the mechanism(s) by which aripiprazole ameliorates A?1-42-induced decreased neurite outgrowth and viability in neuronal cells. Pretreatment with aripiprazole increased Brain-derived neurotrophic factor (BDNF) mRNA and protein expressions in N2a cells. Additionally, phosphorylated casein kinase 2? at Y 255 (P-CK2?) was increased in time- and concentration-dependent manners. Furthermore, A?1-42-induced decreased BDNF and P-CK2? expression were increased over control level by aripiprazole. Subsequently, A?1-42-induced decreased levels of phosphorylated glycogen synthase-3? at Ser9 (P-GSK-3?) and nuclear P-?-catenin (Ser675) were elevated by aripiprazole, which were inhibited by K252A (inhibitor of BDNF receptor) and tetrabromocinnamic acid (TBCA, CK2 inhibitor), indicating that BDNF and P-CK2? activation are implicated in the aripiprazole effects. Expressions of cyclin D1 and insulin-like growth factor 2 (IGF2) mRNA were increased by aripiprazole; even in the presence of A?1-42, which was blocked by K252A and TBCA. In CK2? gene-silenced N2a cells, aripiprazole failed to increase P-GSK-3? and P-?-catenin expressions. Consequently, aripiprazole ameliorated A?1-42-induced attenuation of neurite elongation in HT22 cells, and this effect was blocked by both TBCA and imatinib. Decreased viability induced by A?1-42 was recovered by aripiprazole. These findings provide evidence supporting that aripiprazole can provide an effective therapeutic strategy against A?-induced neurotoxicity in AD-associated psychosis.

SUBMITTER: Park SY

PROVIDER: S-EPMC5746390 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Neuroprotection by aripiprazole against β-amyloid-induced toxicity by P-CK2α activation via inhibition of GSK-3β.

Park So Youn SY Shin Hwa Kyoung HK Lee Won Suk WS Bae Sun Sik SS Kim Koanhoi K Hong Ki Whan KW Kim Chi Dae CD

Oncotarget 20171130 66

Psychosis is reported over 30% of patients with Alzheimer's disease (AD) in clinics. Aripiprazole is an atypical antipsychotic drug with partial agonist activity at the D<sub>2</sub> dopamine and 5-HT<sub>1A</sub> receptors with low side-effect profile. We identified aripiprazole is able to overcome the amyloid-β (Aβ)-evoked neurotoxicity and then increase the cell viability. This study elucidated the mechanism(s) by which aripiprazole ameliorates Aβ1-42-induced decreased neurite outgrowth and v ...[more]

PMID: 29299155

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Project description:Increasing evidence is suggesting that amyloid-β peptide (Aβ), a characteristic of Alzheimer's disease (AD), induces oxidative stress and mitochondrial dysfunction, leading to neuronal death. This study aimed to demonstrate the antioxidant and anti-apoptotic effects of fucoxanthin, a major marine carotenoid found in brown algae, against neuronal injury caused by Aβ. Non-toxic dose range of fucoxanthin (0.1-5 µM) were selected for the neuroprotective study against Aβ25-35. The PC12 cells were pretreated with different concentrations of fucoxanthin for 1 h before being exposed to 10 µM Aβ25-35 for another 24 h. The present results showed that fucoxanthin inhibited Aβ25-35-induced cell death by recovering cell cycle arrest and decreasing intracellular reactive oxygen species (ROS) level. The compound enhanced mitochondrial recovery and regulated apoptosis related proteins including B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax) from Aβ25-35-induced oxidative stress. Concomitantly, fucoxanthin increased the expression of nuclear factor E2-related factor 2 (Nrf2) and its downstream phase II detoxifying enzymes including NADPH: quinone oxidoreductase-1 (NQO-1), glutamate cysteine ligase modifier subunit (GCLm), and thioredoxin reductase 1 (TrxR1), whereas it decreased the expression of cytoplasmic Kelch-like ECH-associated protein 1 (Keap1). Moreover, pretreatment of fucoxanthin reduced Fyn phosphorylation via protein kinase B (Akt)-mediated inhibition of glycogen synthase kinase-3β (GSK-3β), which increased the nuclear localization of Nrf2, suggesting that the compound enhanced Nrf2 expression by the activation of upstream kinase as well as the dissociation of the Nrf2-Keap1 complex. Further validation with a specific phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 demonstrated that the fucoxanthin-mediated Nrf2 antioxidant defense system was directly associated with the Akt/GSK-3β/Fyn signaling pathway. In silico simulation revealed that the oxygen groups of fucoxanthin participated in potent interactions with target markers in the Nrf2 signaling pathway, which may affect the biological activity of target markers. Taken together, the present results demonstrated that the preventive role of fucoxanthin on Aβ-stimulated oxidative injury and apoptosis via Akt/GSK-3β/Fyn signaling pathway. This study would provide a useful approach for potential intervention for AD prevention.

Dataset Information

Neuroprotection by aripiprazole against ?-amyloid-induced toxicity by P-CK2? activation via inhibition of GSK-3?.

Publications

Neuroprotection by aripiprazole against β-amyloid-induced toxicity by P-CK2α activation via inhibition of GSK-3β.

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