Oncotarget

Research Papers:

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

So Youn Park, Hwa Kyoung Shin, Won Suk Lee, Sun Sik Bae, Koanhoi Kim, Ki Whan Hong and Chi Dae Kim _

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Oncotarget. 2017; 8:110380-110391. https://doi.org/10.18632/oncotarget.22777

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Abstract

So Youn Park1,2, Hwa Kyoung Shin3, Won Suk Lee1, Sun Sik Bae1,2, Koanhoi Kim1, Ki Whan Hong2 and Chi Dae Kim1,2

1Department of Pharmacology, School of Medicine, Pusan National University, Gyeongsangnam-do 50612, Republic of Korea

2Gene & Cell Therapy Research Center for Vessel-associated Diseases, Pusan National University, Gyeongsangnam-do 50612, Republic of Korea

3Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Gyeongsangnam-do 50612, Republic of Korea

Correspondence to:

Chi Dae Kim, email: chidkim@pusan.ac.kr

Keywords: aripiprazole; alzheimer’s disease; Wnt/β-catenin pathway; GSK-3β; CK2α

Received: May 13, 2017     Accepted: November 19, 2017     Published: November 30, 2017

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-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 viability in neuronal cells. Pretreatment with aripiprazole increased Brain-derived neurotrophic factor (BDNF) mRNA and protein expressions in N2a cells. Additionally, phosphorylated casein kinase 2α at Y 255 (P-CK2α) was increased in time- and concentration-dependent manners. Furthermore, Aβ1-42-induced decreased BDNF and P-CK2α expression were increased over control level by aripiprazole. Subsequently, Aβ1-42-induced decreased levels of phosphorylated glycogen synthase-3β at Ser9 (P-GSK-3β) and nuclear P-β-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-CK2α 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 Aβ1-42, which was blocked by K252A and TBCA. In CK2α gene-silenced N2a cells, aripiprazole failed to increase P-GSK-3β and P-β-catenin expressions. Consequently, aripiprazole ameliorated Aβ1-42-induced attenuation of neurite elongation in HT22 cells, and this effect was blocked by both TBCA and imatinib. Decreased viability induced by Aβ1-42 was recovered by aripiprazole. These findings provide evidence supporting that aripiprazole can provide an effective therapeutic strategy against Aβ-induced neurotoxicity in AD-associated psychosis.


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