Neuroprotection by aripiprazole against β-amyloid-induced toxicity by P-CK2α activation via inhibition of GSK-3β
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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
Chi Dae Kim, email: [email protected]
Keywords: aripiprazole; alzheimer’s disease; Wnt/β-catenin pathway; GSK-3β; CK2α
Received: May 13, 2017 Accepted: November 19, 2017 Published: November 30, 2017
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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